Novel pyrrolodihydroisoquinolines useful in the treatment of cancer

ABSTRACT

The invention relates to novel pyrrolodihydroisoquinoline derivatives, which are efficacious inhibitors of cellular (hyper)proliferation and/or inducers of apoptosis in cancer cells.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel pyrrolodihydroisoquinoline derivatives,which are used in the pharmaceutical industry for the production ofpharmaceutical compositions.

KNOWN TECHNICAL BACKGROUND

Cancer chemotherapy was established with the alkylating agentCyclophosphamide (Endoxan®), an oxazaphosphorin pro-drug activatedpreferentially in the tumor. The target of alkylating agents likeCyclophosphamide is DNA and the concept, that cancer cells withuncontrolled proliferation and a high mitotic index are killedpreferentially, proved to be very sucessfull. Standard cancerchemotherapeutic drugs finally kill cancer cells upon induction ofprogrammed cell death (“apoptosis”) by targeting basic cellularprocesses and molecules. These basic cellular processes and moleculesinclude RNA/DNA (alkylating and carbamylating agents, platin analogs andtopoisomerase inhibitors), metabolism (drugs of this class are namedanti-metabolites and examples are folic acid, purin and pyrimidineantagonists) as well as the mitotic spindle apparatus with 4-tubulinheterodimers as the essential component (drugs are categorized intostabilizing and destabilizing tubulin inhibitors; examples areTaxol/Paclitaxel®, Docetaxel/Taxotere® and vinca alkaloids).

1. Prior Art

The international applications WO 02/48144, WO 03/014115, WO 03/014116,WO 03/014117 and WO 03/051877 disclose pyrrolodihydroisoquinolinederivatives with PDE10 inhibitory activity. The U.S. Pat. No. 5,965,575discloses pyrrolodihydroisoquinoline derivatives as 5HT_(1B)antagonists.

2. Description of the invention

It has now been found that the pyrroloisoquinoline derivatives, whichare described in greater details below, differ from prior art compoundsby unanticipated structural features and have surprising andparticularly advantageous properties.

In more detail, thus, for example, it has been unexpectedly andunanticipatedly found that the pyrrolodihydroisoquinoline derivatives,which are described in greater details below, are potent and highlyefficacious inhibitors of cellular proliferation and inducers ofapoptosis in cancer cells. Therefore, yet unanticipatedly, thesepyrrolodihydroisoquinoline derivatives can be useful for treatinghyperproliferative diseases and/or disorders responsive to the inductionof apoptosis, in particular cancer.

In this context, in further more surprising detail, it has beenparticularly found that the pyrrolodihydroisoquinoline derivatives,which are described in greater details below, stand out from the generalclass of the pyrrolodihydroisoquinolines, whose original property isinhibition of PDE10, in interesting and valueable properties, such ase.g. those mentioned afore, i.e. inhibiting cellular(hyper)proliferation and inducing apoptosis in cancer cells, which makethem particularly interesting for treating e.g. hyperproliferativediseases and/or disorders responsive to the induction of apoptosis, inparticular cancer.

The invention thus relates to compounds of formula I

in which

-   R1 is halogen, nitro, amino, mono- or di-1-4C-alkylamino,    1-4C-alkyl, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is hydrogen, halogen or 1-4C-alkoxy,-   R3 is hydrogen or 1-4C-alkoxy, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a 1-2C-alkylenedioxy bridge, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a 1-2C-alkylenedioxy bridge and R3 is hydrogen,    or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge and R3 is hydrogen,-   R4 is hydrogen, fluorine, chlorine, 1-4C-alkyl, trifluoromethyl,    cyclopropyl, cyano, 1-4C-alkoxycarbonyl or —CH₂O—R411, in which-   R411 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4-alkyl or    1-4C-alkylcarbonyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen, or-   R4 is hydrogen, fluorine, chlorine or 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, amino, formyl, or 1-4C-alkyl substituted by R61,    in which-   R61 is 1-4C-alkoxycarbonyl, carboxyl, 1-4C-alkoxy, hydroxyl, halogen    or —N(R611)R612, in which-   R611 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or    3-7C-cycloalkyl-1-4C-alkyl,-   R612 is hydrogen or 1-4C-alkyl, or-   R611 and R612 together and with inclusion of the nitrogen atom to    which they are bound form a radical Het1, in which-   Het1 is a 5- to 7-membered saturated heterocyclic ring radical    comprising one nitrogen atom, to which R611 and R612 are bound, and,    optionally, one further heteroatom selected from a group consisting    of nitrogen, oxygen and sulfur, and optionally substituted by R613    on a ring nitrogen atom, in which-   R613 is 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,    hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, amino-2-4C-alkyl, mono-    or di-1-4C-alkylamino-2-4C-alkyl, formyl, pyridyl or pyrimidinyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, naphthyl, or R76- and/or    R77-substituted naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5 to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl,    1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino,    1-4C-alkylsulphonylamino, arylsulphonylamino, 1-4C-alkoxycarbonyl,    carboxyl, 1-4C-alkylthio, aryloxy-2-4C-alkoxy, aryloxy-1-4C-alkyl,    aryloxy, aryl-1-4C-alkoxy, aryl, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkoxy, amino-2-4C-alkoxy,    mono- or di-1-4C-alkylamino-2-alkoxy, or completely or predominantly    fluorine substituted 1-4C-alkoxy, in which-   aryl is phenyl or R711-substituted phenyl, in which-   R711 is halogen, 1-4C-alkyl, 1-4C-alkoxy, nitro or cyano,-   R72 is halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is halogen, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, cyano,    amino, mono- or di-1-4C-alkylamino, 1-4C-alkoxycarbonyl, morpholino,    carboxyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl or halogen,-   R76 is halogen, hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, carboxyl or    1-4C-alkoxycarbonyl,-   R77 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,    3-7C-cycloalkyl-1-4C-alkyl, phenyl or phenyl-1-4C-alkyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl, piperidinyl, morpholinyl or    N-(1-4C-alkyl)-piperazinyl,-   R9 is 1-4C-alkyl;    under the provisio, that this subgroup of compounds of formula I,    wherein the combination of all of the following restrictions a.) to    c.) apply, is thereof disclaimed:-   a.) the substitution pattern of the left R1- and/or R2- and/or    R3-substituted benzo ring of the dihydroisoquinoline moiety of the    pyrrolodihydroisoquinoline scaffold shown in formula I is as    follows:    -   in which    -   R′ and R″ can be bonded at any possible position of the benzo        ring, and    -   R′ is hydroxyl, 1-4C-alkoxy or trifluoromethoxy,    -   R″ is hydrogen or 1-4C-alkoxy,    -   or R′ and R″ bound to the benzo ring moiety in ortho-position to        each other together form a 1-2C-alkylenedioxy bridge,        and-   b.) R4 is hydrogen, and    -   R41 is hydrogen, and    -   R5 is hydrogen, and    -   R51 is hydrogen,        and-   c.) R8 is —C(O)—OR9, in which    -   R9 is 1-4C-alkyl;        and to the salts, stereoisomers, hydrates and hydrates of the        salts of these compounds.

The invention further relates in a first aspect (aspect a) to compoundsof formula I, in which

-   R1 is halogen, nitro, amino, mono- or di-1-4C-alkylamino,    1-4C-alkyl, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is hydrogen, halogen or 1-4C-alkoxy,-   R3 is hydrogen or 1-4C-alkoxy, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a 1-2C-alkylenedioxy bridge, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a 1-2C-alkylenedioxy bridge and R3 is hydrogen,    or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge and R3 is hydrogen,-   R4 is hydrogen, fluorine, chlorine, 1-4C-alkyl, trifluoromethyl,    cyclopropyl, cyano, 1-4C-alkoxycarbonyl or —CH₂O—R411, in which-   R411 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4-alkyl or    1-4C-alkylcarbonyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,    or-   R4 is hydrogen, fluorine, chlorine or 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, amino, formyl, or 1-4C-alkyl substituted by R61,    in which-   R61 is 1-4C-alkoxycarbonyl, carboxyl, 1-4C-alkoxy, hydroxyl, halogen    or —N(R611)R612, in which-   R611 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or    3-7C-cycloalkyl-1-4C-alkyl,-   R612 is hydrogen or 1-4C-alkyl, or-   R611 and R612 together and with inclusion of the nitrogen atom to    which they are bound form a radical Het1, in which-   Het1 is a 5- to 7-membered saturated heterocyclic ring radical    comprising one nitrogen atom, to which R611 and R612 are bound, and,    optionally, one further heteroatom selected from a group consisting    of nitrogen, oxygen and sulfur, and optionally substituted by R613    on a ring nitrogen atom, in which-   R613 is 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,    hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, amino-2-4C-alkyl, mono-    or di-1-4C-alkylamino-2-4C-alkyl, formyl, pyridyl or pyrimidinyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, naphthyl, or R76- and/or    R77-substituted naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5 to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl,    14-alkoxy, amino, mono- or di-1-4C-alkylamino,    1-4C-alkylsulphonylamino, arylsulphonylamino, 1-4C-alkoxycarbonyl,    carboxyl, 1-4C-alkylthio, aryloxy-2-4C-alkoxy, aryloxy-1-4C-alkyl,    aryloxy, aryl-1-4C-alkoxy, aryl, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkoxy, amino-2-4C alkoxy,    mono- or di-1-4C-alkylamino-2-4C-alkoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy, in which-   aryl is phenyl or R711-substituted phenyl, in which-   R711 is halogen, 1-4C-alkyl, 1-4C-alkoxy, nitro or cyano,-   R72 is halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is halogen, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, cyano,    amino, mono- or di-1-4C-alkylamino, 1-4C-alkoxycarbonyl, morpholino,    carboxyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl or halogen,-   R76 is halogen, hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, carboxyl or    1-4C-alkoxycarbonyl,-   R77 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is phenyl, phenylcarbonyl or —C(O)—N(R82)R83, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,    3-7C-cycloalkyl-1-4C-alkyl, phenyl or phenyl-1-4C-alkyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl, piperidinyl, morpholinyl or    N-(1-4C-alkyl)-piperazinyl,    and to the salts, stereoisomers, hydrates and hydrates of the salts    of these compounds.

The invention further relates in a second aspect (aspect b) to compoundsof formula I, in which

-   R1 is halogen, nitro, amino, mono- or di-1-4C-alkylamino,    1-4C-alkyl, 1-4C-alkoxy-2-4C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,    with the provisio that R1 is not trifluoromethoxy,-   R2 is hydrogen, halogen or 1-4C-alkoxy,-   R3 is hydrogen or 1-4C-alkoxy, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a 1-2C-alkylenedioxy bridge, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a 1-2C-alkylenedioxy bridge and R3 is hydrogen,    or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge and R3 is hydrogen,-   R4 is hydrogen, fluorine, chlorine, 1-4C-alkyl, trifluoromethyl,    cyclopropyl, cyano, 1-4C-alkoxycarbonyl or CH₂O—R411, in which-   R411 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or    1-4C-alkylcarbonyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,    or-   R4 is hydrogen, fluorine, chlorine or 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, amino, formyl, or 1-4C-alkyl substituted by R61,    in which-   R61 is 1-4C-alkoxycarbonyl, carboxyl, 1-4C-alkoxy, hydroxyl, halogen    or —N(R611)R612, in which-   R611 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or    3-7C-cycloalkyl-1-4C-alkyl,-   R612 is hydrogen or 1-4C-alkyl, or-   R611 and R612 together and with inclusion of the nitrogen atom to    which they are bound form a radical Het1, in which-   Het1 is a 5 to 7-membered saturated heterocyclic ring radical    comprising one nitrogen atom, to which R611 and R612 are bound, and,    optionally, one further heteroatom selected from a group consisting    of nitrogen, oxygen and sulfur, and optionally substituted by R613    on a ring nitrogen atom, in which-   R613 is 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,    hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, amino-2-4C-alkyl, mono-    or di-1-4C-alkylamino-2-4C-alkyl, formyl, pyridyl or pyrimidinyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, naphthyl, or R76- and/or    R77-substituted naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5 to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl,    1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino,    1-4C-alkylsulphonylamino, arylsulphonylamino, 1-4C-alkoxycarbonyl,    carboxyl, 1-4C-alkylthio, aryloxy-2-4C-alkoxy, aryloxy-1-4C-alkyl,    aryloxy, aryl-1-4C-alkoxy, aryl, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkoxy-1 alkyl, hydroxy-2-4C-alkoxy, amino-2-4C-alkoxy, mono-    or di-1-4C-alkylamino-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy, in which aryl is phenyl or    R711-substituted phenyl, in which-   R711 is halogen, 1-4C-alkyl, 1-4C-alkoxy, nitro or cyano,-   R72 is halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is halogen, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, cyano,    amino, mono- or di-1-4C-alkylamino, 1-4C-alkoxycarbonyl, morpholino,    carboxyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl or halogen,-   R76 is halogen, hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, carboxyl or    1-4C-alkoxycarbonyl,-   R77 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,    3-7C-cycloalkyl-1-4C-alkyl, phenyl or phenyl-1-4C-alkyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl, piperidinyl, morpholinyl or    N-(1-4C-alkyl)-piperazinyl,-   R9 is 1-4C-alkyl,    and to the salts, stereoisomers, hydrates and hydrates of the salts    of these compounds.

The invention further relates in a third aspect (aspect c) to compoundsof formula I, in which

-   R1 is halogen, nitro, amino, mono- or di-1-4C-alkylamino,    1-4C-alkyl, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is halogen or 1-4C-alkoxy,-   R3 is 1-4C-alkoxy, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a 1-2C-alkylenedioxy bridge, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge,-   R4 is hydrogen, fluorine, chlorine, 1-4C-alkyl, trifluoromethyl,    cyclopropyl, cyano, 1-4C-alkoxycarbonyl or —CH₂—O—R411, in which-   R411 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4-alkyl or    1-4C-alkylcarbonyl,-   R41 is hydrogen or 1 alkyl,-   R5 is hydrogen,-   R51 is hydrogen,    or-   R4 is hydrogen, fluorine, chlorine or 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-4C-alkyl, amino, formyl, or 1-4C-alkyl substituted by R61,    in which-   R61 is 1-4C-alkoxycarbonyl, carboxyl, 1-4C-alkoxy, hydroxyl, halogen    or —N(R611)R612, in which-   R611 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or    3-7C-cycloalkyl-1-4C-alkyl,-   R612 is hydrogen or 1-4C-alkyl, or-   R611 and R612 together and with inclusion of the nitrogen atom to    which they are bound form a radical Het1, in which-   Het1 is a 5- to 7-membered saturated heterocyclic ring radical    comprising one nitrogen atom, to which R611 and R612 are bound, and,    optionally, one further heteroatom selected from a group consisting    of nitrogen, oxygen and sulfur, and optionally substituted by R613    on a ring nitrogen atom, in which-   R613 is 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,    hydroxy-2-4C-alkyl, 1C-alkoxy-2-4C-alkyl, amino-2-4C-alkyl, mono- or    di-1-4C-alkylamino-2-4C-alkyl, formyl, pyridyl or pyrimidinyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74 and/or R75-substituted Het2, naphthyl, or R76- and/or    R77-substituted naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5 to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl,    1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino,    1-4C-alkylsulphonylamino, arylsulphonylamino, 1-4C-alkoxycarbonyl,    carboxyl, 1-4C-alkylthio, aryloxy-2-4C-alkoxy, aryloxy-1-4C-alkyl,    aryloxy, aryl-1-4C-alkoxy, aryl, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkoxy, amino-2-4C-alkoxy,    mono- or di-1-4C-alkylamino-2-4C-alkoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy, in which-   aryl is phenyl or R711-substituted phenyl, in which-   R711 is halogen, 1-4C-alkyl, 1-4C-alkoxy, nitro or cyano,-   R72 is halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is halogen, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, cyano,    amino, mono- or di-1-4C-alkylamino, 1-4C-alkoxycarbonyl, morpholino,    carboxyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl or halogen,-   R76 is halogen, hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, carboxyl or    1-4C-alkoxycarbonyl,-   R77 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,    3-7C-cycloalkyl-1-4C-alkyl, phenyl or phenyl-1-4C-alkyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl, piperidinyl, morpholinyl or    N-1-4C-alkyl)-piperazinyl,-   R9 is 1-4C-alkyl,    and to the salts, stereoisomers, hydrates and hydrates of the salts    of these compounds.

The invention further relates in a fourth aspect (aspect d) to compoundsof formula I, in which

-   R1 is halogen, nitro, amino, mono- or di-1-4C-alkylamino,    1-4C-alkyl, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is hydrogen, halogen or 1-4C-alkoxy,-   R3 is hydrogen or 1-4C-alkoxy, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a 1-2C-alkylenedioxy bridge, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a 1-2C-alkylenedioxy bridge and R3 is hydrogen,    or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge and R3 is hydrogen,-   R4 is fluorine, chlorine, 1-4C-alkyl, trifluoromethyl, cyclopropyl,    cyano, 1-4C-alkoxycarbonyl or —CH₂—O—R411, in which-   R411 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or    1-4C-alkylcarbonyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, amino, formyl, or 1-4C-alkyl substituted by R61,    in which-   R61 is 1-4C-alkoxycarbonyl, carboxyl, 1-4C-alkoxy, hydroxyl, halogen    or —N(R611)R612, in which-   R611 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or    3-7C-cycloalkyl-1-4C-alkyl,-   R612 is hydrogen or 1-4C-alkyl, or-   R611 and R612 together and with inclusion of the nitrogen atom to    which they are bound form a radical Het1, in which-   Het1 is a 5- to 7-membered saturated heterocyclic ring radical    comprising one nitrogen atom, to which R611 and R612 are bound, and,    optionally, one further heteroatom selected from a group consisting    of nitrogen, oxygen and sulfur, and optionally substituted by R613    on a ring nitrogen atom, in which-   R613 is 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,    hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, amino-2-4C-alkyl, mono-    or di-1-4C-alkylamino-2-4C-alkyl, formyl, pyridyl or pyrimidinyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74 and/or R75-substituted Het2, or naphthyl, or R76- and/or    R77-substituted naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5 to 10-membered heteroaryl    radical composing one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl,    1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino,    1-4C-alkylsulphonylamino, arylsulphonylamino, 1-4C-alkoxycarbonyl,    carboxyl, 1-4C-alkylthio, aryloxy-2-4C-alkoxy, aryloxy-1-4C-alkyl,    aryloxy, aryl-1-4C-alkoxy, aryl, 1-4C-alkoxy-2-4C-alkoxy,    1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkoxy, amino-2-4C-alkoxy,    mono- or di-1-4C-alkylamino-2-4C-alkoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy, in which-   aryl is phenyl or R711-substituted phenyl, in which-   R711 is halogen, 1-4C-alkyl, 1-4C-alkoxy, nitro or cyano,-   R72 is halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is halogen, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, cyano,    amino, mono- or di-1-4C-alkylamino, 1-4C-alkoxycarbonyl, morpholino,    carboxyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl or halogen,-   R76 is halogen, hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, carboxyl or    1-4C-alkoxycarbonyl,-   R77 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,    3-7C-cycloalkyl-1-4C-alkyl, phenyl or phenyl-1-4C-alkyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl, piperidinyl, morpholinyl or    N-(1-4C-alkyl)-piperazinyl,-   R9 is 1-4C-alkyl,    and to the salts, stereoisomers, hydrates and hydrates of the salts    of these compounds.

1-4C-Alkyl represents a straight-chain or branched alkyl radical having1 to 4 carbon atoms. Examples which may be mentioned are the butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably theethyl and methyl radicals.

2-4C-Alkyl represents a straight-chain or branched alkyl radical having2 to 4 carbon atoms. Examples which may be mentioned are the butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably theethyl radical.

1-6C-Alkyl represents a straight-chain or branched alkyl radical having1 to 6 carbon atoms. Examples which may be mentioned are the hexyl,isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl,isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl or methylradicals.

1-4C-Alkoxy represents radicals which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 1 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxyand methoxy radicals.

1-4C-Alkylthio represents radicals which, in addition to the sulfuratom, contain a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples which may be mentioned are the ethylthio and themethylthio radicals.

2-4C-Alkoxy represents radicals which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 2 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxyradical.

3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of whichcyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl andcyclopentyl are preferred.

3-7C-cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of whichcyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy arepreferred.

3-7C-Cycloalkyl-1-4C-alkyl represents one of the abovementioned1-4C-alkyl radicals, which is substituted by one of the abovementioned3-7C-cycloalkyl radicals. Examples which may be mentioned are thecyclopropylmethyl, the cyclohexylethyl and the cyclohexylmethylradicals.

As completely or predominantly fluorine-substituted 1-4C-alkoxy, forexample, the 2,2,3,3,3-penta-fluoropropoxy, the perfluoroethoxy, the1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably thedifluoromethoxy radicals may be mentioned. “Predominantly” in thisconnection means that more than half of the hydrogen atoms of the1-4C-alkoxy radicals are replaced by fluorine atoms.

1-4C-Alkoxy-2-4C-alkoxy represents one of the abovementioned 2-4C-alkoxyradicals, which is substituted by one of the abovementioned 1-4C-alkoxyradicals. Examples which may be mentioned are the 2-methoxyethoxy,2-ethoxyethoxy and the 2-isopropoxyethoxy radicals.

1-4C-Alkoxy-2-4C-alkyl represents one of the abovementioned 2-4C-alkylradicals, which is substituted by one of the abovementioned 1-4C-alkoxyradicals. Examples which may be mentioned are the 2-methoxyethyl and the2-isopropoxyethyl radicals.

1-4C-Alkoxy-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals, which is substituted by one of the abovementioned 1-4C-alkoxyradicals. Examples which may be mentioned are the 2-methoxyethyl and2-isopropoxyethyl radicals.

1-2C-Alkylenedioxy represents, for example, the methylenedioxy[—O—CH₂—O—] and the ethylenedioxy [—O—CH₂—CH₂—O—] radicals.

As completely or predominantly fluorine-substituted 1-2C-alkylenedioxybridge, for example, the difluoromethylenedioxy [—O—CF₂—O—] radical maybe mentioned. “Predominantly” in this connection means that more thanhalf of the hydrogen atoms of the 1-4C-alkylenedioxy radical arereplaced by fluorine atoms.

Phenyl-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals, which is substituted by a phenyl radical. Examples which maybe mentioned are the phenethyl and the benzyl radicals.

1-4C-alkoxycarbonyl represents a radical which, in addition to thecarbonyl group, contains one of the abovementioned 1-4C-alkoxy radicals.Examples which may be mentioned are the methoxycarbonyl andethoxycarbonyl radicals.

1-4C-Alkylcarbonyl represents a radical which, in addition to thecarbonyl group, contains one of the abovementioned 1-4C-alkyl radicals.An example which may be mentioned is the acetyl radical.

1-4C-Alkylene is a straight-chain alkylene radical such as, for example,the methylene (—CH₂—) or, particularly, the trimethylene (—CH₂—CH₂—CH₂—)or the tetramethylene (—CH₂CH₂—CH₂—CH₂—) radical.

Halogen within the meaning of the invention is bromine and, preferably,chlorine and fluorine.

Hydroxy-2-4C-alkyl stands for one of the abovementioned 2-4C-alkylradicals which is substituted by a hydroxyl group. Examples which may bementioned are the 2-hydroxyethyl and 3-hydroxypropyl radicals.

Hydroxy-2-4C-alkoxy stands for one of the abovementioned 2-4C-alkoxyradicals which is substituted by a hydroxyl group. Examples which may bementioned are the 2-hydroxyethoxy and 3-hydroxypropoxy radicals.

Amino-2-4C-alkyl stands for one of the abovementioned 2-4C-alkylradicals which is substituted by an amino group. Examples which may bementioned are the 2-aminoethyl and 3-aminopropyl radicals.

Amino-2-4C-alkoxy stands for one of the abovementioned 2-4C-alkoxyradicals which is substituted by an amino group. Examples which may bementioned are the 2-aminoethoxy and 3-aminopropoxy radicals.

In addition to the nitrogen atom, mono- or di-1-4C-alkylamino radicalscontain one or two of the abovementioned 1-4C-alkyl radicals.Di-1-4C-alkylamino is to be emphasized and here, in particular,dimethyl-, diethyl- and diisopropylamino.

Mono- or Di-1-4C-alkylamino-2-4C-alkyl stands for one of theabovementioned 2-4C-alkyl radicals which is substituted by one of theabovementioned mono- or di-1-4C-alkylamino radicals. Examples which maybe mentioned are the 2-dimethylaminoethyl and 3-dimethylaminopropylradicals.

Mono- or Di-1-4C-alkylamino-2-4C-alkoxy stands for one of theabovementioned 2-4C-alkoxy radicals which is substituted by one of theabovementioned mono- or di-1-4C-alkylamino radicals. Examples which maybe mentioned are the 2-dimethylaminoethoxy and 3-dimethylaminopropoxyradicals.

1-4C-Alkylsulfonyl is a sulfonyl group to which one of theabovementioned 1-4C-alkyl radicals is bonded. An example is themethanesulfonyl radical (CH₃SO₂—).

1-4C-Alkylsulfonylamino is an amino group which is substituted by one ofthe abovementioned 1-4C-alkylsulfonyl radicals. An example is themethanesulfonylamino radical (CH₃SO₂NH—).

Aryl radicals referred to herein, including those forming part of othergroups or radicals, include phenyl or R711-substituted phenyl radicals.

Aryloxy stands for phenoxy or R711-substituted phenoxy.

Aryl-1-4C-alkoxy stands for one of the abovementioned 1-4C-alkoxyradicals, which is substituted by one of the abovementioned arylradicals. Examples which may be mentioned are the 2-arylethoxy (e.g.phenethoxy) and the arylmethoxy (e.g. benzyloxy) radicals.

Aryloxy-2-4C-alkoxy stands for one of the abovementioned 2-4C-alkoxyradicals, which is substituted by one of the abovementioned aryloxyradicals. An example which may be mentioned is the 2-aryloxyethoxy (e.g.2-phenoxyethoxy) radical.

Aryloxy-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals, which is substituted by one of the abovementioned aryloxyradicals. Examples which may be mentioned are the 2-aryloxyethyl (e.g.2-phenoxyethyl) and the aryloxymethyl (e.g. phenoxymethyl) radicals.

Het1 refers to a 5- to 7-membered saturated heterocyclic ring radicalcomprising one nitrogen atom, to which R611 and R612 are bound, and,optionally, one further heteroatom selected from a group consisting ofnitrogen, oxygen and sulfur, and optionally substituted by R613 on aring nitrogen atom. Examples for Het2 include e.g. piperidin-1-yl,4-methyl-piperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholinyl,pyrrolidin-1-yl, piperazin-1-yl, imidazolidin-1-yl, thiomorpholinyl,homopiperidin-1-yl, homopiperazin-1-yl,4-N-(1-4C-alkyl)-homopiperazin-1-yl or piperazinyl substituted on a ringnitrogen atom by R613 [4-N—(R613)-piperazin-1-yl] such as, for example,4-N-(1-4C-alkyl)-piperazin-1-yl,4-N-(hydroxy-2-4C-alkyl)-piperazin-1-yl,4-N-(dimethylamino-2-4C-alkyl)-piperazin-1-yl,4-N-(3-6C-cycloalkyl)-piperazin-1-yl, 4-N-formyl-piperazin-1-yl,4-N-(pyridin-4-yl)-piperazin-1-yl, 4-N-(pyrimidin-2-yl)-piperazin-1-ylor 4-N-(3-6C-cycloalkylmethyl)-piperazin-1-yl.

Het2 refers to a monocyclic or fused bicyclic 5 to 10-memberedheteroaryl (heteroaromatic) radical comprising one to three heteroatoms,each of which is selected from a group consisting of nitrogen, oxygenand sulfur, and includes, for example, without being restricted tofuranyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, triazolyl, thiadiazolyl,oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzo-fusedanalogues thereof, such as, for example, quinazolinyl, quinoxalinyl,cinnolinyl, quinolyl, isoquinolyl, indolyl, isoindolyl, indazolyl,benzothiophenyl, benzofuranyl, benzoxazolyl, benzothiazolyl orbenzimidazolyl, or naphthyridinyl, phthalazinyl, imidazopyridinyl,purinyl, pteridinyl or imidazopyridazinyl. The monocyclic 5- to6-membered radicals, such as, for example, furanyl, thiophenyl,pyrrolyl, pyrimidinyl and pyridinyl, and quinolinyl and indolyl are moreworthy to be mentioned. In particular worthy to be mentioned areindolyl, quinolinyl and pyridinyl. In more particular worthy to bementioned are quinolyl and pyridinyl, especially quinolin-4-yl and,particularly, pyridin-4-yl.

N-(1-4C-alkyl)-piperazinyl stands for the piperazin-1-yl radicalsubstituted by one of the abovementioned 1-4C-alkyl radicals on the 4Nring nitrogen atom.

Naphthyl includes naphthalene-1-yl and naphthalene-2-yl.

The term Het2 includes all the possible isomeric forms thereof, inparticular the positional isomers thereof. Thus, e.g. pyridinyl orpyridyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

Constituents which are substituted as described herein may besubstituted, unless otherwise noted, at any possible position.

The substituents R1, R2 and/or R3 may be attached, unless otherwisenoted, at any position of the benzo moiety of thepyrrolodihydroisoquinoline ring.

Suitable salts for compounds of the formula I—depending onsubstitution—are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically tolerableinorganic and organic adds and bases customarily used in pharmacy. Thosesuitable are, on the one hand, water-insoluble and, particularly,water-soluble acid addition salts with adds such as, for example,hydrochloric add, hydrobromic acid, phosphoric acid, nitric acid,sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric add, sulphosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic add, stearic acid, toluenesulphonicacid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

On the other hand, salts with bases are—depending on substitution—alsosuitable. As examples of salts with bases are mentioned the lithium,sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium,meglumine or guanidinium salts, here, too, the bases being employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothe invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to experts knowledge the compounds of the invention as well astheir salts may contain, e.g. when isolated in crystalline form, varyingamounts of solvents. Included within the scope of the invention aretherefore all solvates and in particular all hydrates of the compoundsof formula I as well as all solvates and in particular all hydrates ofthe salts of the compounds of formula I.

Depending on substitution the compounds of formula I can be chiralcompounds having, for example, chiral centers and/or chiral axes due tohindered rotation about single bonds. Chiral axes can be present inparticular in those compounds according to the invention, in which R7 isa bicyclic ring, or a monocyclic ring substituted in the ortho positionwith respect to the binding position in which said monocyclic ring isbonded to the pyrrolo[2.1-a]isoquinoline ring system. The inventiontherefore includes all conceivable pure diastereomers and pureenantiomers and mixtures thereof in any mixing ratio including theracemates. The diastereomer mixtures can be separated into theindividual isomers by chromatographic processes. The enantiomers can beseparated in a known manner (e.g. by chromatographic processes on chiralphases or by resolution).

In the context of this invention, the term “hyperproliferation” andanalogous terms are used to describe aberrant/dysregulated cellulargrowth, a hallmark of diseases like cancer. This hyperproliferationmight be caused by single or multiple cellular/molecular alterations inrespective cells and can be, in context of a whole organism, of benignor malignant behaviour. The phrase “inhibition of cell proliferation” isused to denote an ability of the compound to retard the growth of a cellcontacted with that compound as compared to cells not contacted withthat compound. Most preferable this inhibition of cell proliferation is100%, meaning that proliferation of all cells is stopped and/or cellsundergo programmed cell death. In some preffered embodiments thecontacted cell is a neoplastic cell. A neoplastic cell is defined as acell with aberrant cell proliferation. A benign neoplasia is describedby hyperproliferation of cells, incapable of forming an aggressive,metastasizing tumor in-vivo. In contrast, a malignant neoplasia isdescribed by cells with different cellular and biochemicalabnormalities, capable of forming tumor metastasis. The aquiredfunctional abnormalities of malignant neoplastic cells (also defined as“hallmarks of cancer”) are replicative potential (“hyperproliferation”),self-sufficiency in growth signals, insensitivity to anti-growthsignals, evasion from apoptosis, sustained angiogenesis and tissueinvasion and metastasis.

The term “inducer of apoptosis” and analogous terms are used to identifya compound which excecutes programmed cell death in cells contacted withthat compound. Apoptosis is defined by complex biochemical events withinthe contacted cell, such as the activation of cystein specificproteinases (“caspases”) and the fragmentation of chromatin. Inductionof apoptosis in cells contacted with the compound might not necessarilycoupled with inhibition of cell proliferation. Preferably, theinhibition of cell proliferation and/or induction of apoptosis isspecific to cells with aberrant cell growth (hyperproliferation). Thus,compared to cells with aberrant cell growth, normal proliferating orarrested cells are less sensitive or even insensitive to theproliferation inhibiting or apoptosis inducing activity of the compound.Finally, the term “cytotoxic” is used in a more general sense toidentify compounds which kill cells by various mechanisms, including theinduction of apoptosis/programmed cell death in a cell cycle dependentor cell-cycle independent manner.

A special subaspect (subaspect 1) of aspects a, b, c and d refers tocompounds of formula I according to aspects a, b, c and d, in which noneof R1, R2 and R3 is bound to the 10-position of thepyrrolo[2.1-a]isoquinoline ring.

Numbering:

A further special subaspect (subaspect 2) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R8 is phenyl, phenylcarbonyl or —C(O)—N(R82)R83, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,    3-7C-cycloalkyl-1-4C-alkyl, phenyl or phenyl-1-4C-alkyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl, piperidinyl, morpholinyl or    N-(1-4C-alkyl)-piperazinyl.

A further special subaspect (subaspect 3) of aspects a, b, c, and drefers to compounds of formula I according to aspects a, b, c and d, inwhich.

-   R1 is halogen, nitro, amino, mono- or di-1-4C-alkylamino,    1-4C-alkyl, 1-4C-alkoxy-2-4C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,    with the provisio that R1 is not trifluoromethoxy,-   R2 is hydrogen, halogen or 1-4C-alkoxy,-   R3 is hydrogen or 1-4C-alkoxy, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a 1-2C-alkylenedioxy bridge, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a 1-2C-alkylenedioxy bridge and R3 is hydrogen,    or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge and R3 is hydrogen.

A further special subaspect (subaspect 4) of aspects a, c, d and erefers to compounds of formula I according to aspects a, c and d, inwhich

-   R1 is halogen, nitro, amino, mono- or di-1-4C-alkylamino,    1-4C-alkyl, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is halogen or 1-4C-alkoxy,-   R3 is 1-4C-alkoxy, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a 1-2C-alkylenedioxy bridge, or-   R2 and R3 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge.

A further special subaspect (subaspect 5) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R4 is fluorine, chlorine, 1-4C-alkyl, trifluoromethyl, cyclopropyl,    cyano, 1-4C-alkoxycarbonyl or —CH₂—O—R411, in which-   R411 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or    1-4C-alkylcarbonyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen.

A further special subaspect (subaspect 6) of aspects a, b and d refersto compounds of formula I according to aspects a, b and d, in which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkoxy, or    completely or predominantly fluorine-substituted 1-4C-alkoxy,    with the provisio that R1 is not trifluoromethoxy,-   R2 is hydrogen or 1-4C-alkoxy,-   R3 is hydrogen or 1-4C-alkoxy, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge and R3 is hydrogen.

A further special subaspect (subaspect 7) of said aspects a, c and drefers to compounds of formula I according to aspects a, c and d, inwhich

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy.

A further special subaspect (subaspect 8) of said aspects a, c and drefers to compounds of formula I according to aspects a, c and d, inwhich

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is halogen,-   R3 is 1-4C-alkoxy.

A further special subaspect (subaspect 9) of said aspects a and d refersto compounds of formula I according to aspects a and d, in which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is hydrogen.

A further special subaspect (subaspect 10) of said aspects a and drefers to compounds of formula I according to aspects a and d, in which

-   R1 is 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is hydrogen.

A further special subaspect (subaspect 11) of said aspects a and drefers to compounds of formula I according to aspects a and d, in which

-   R1 is halogen or 1-2C-alkoxy,-   R2 is hydrogen or 1-2C-alkoxy,-   R3 is 1-2C-alkoxy.

A further special subaspect (subaspect 12) of said aspects a, c and drefers to compounds of formula I according to aspects a, c and d, inwhich

-   R1 is 1-2C-alkoxy,-   R2 is 1-2C-alkoxy,-   R3 is 1-2C-alkoxy.

Compounds according to subaspect 12 more worthy to be mentioned arethose, in which none of R1, R2 and R3 is bound to the 10-position of thepyrrolo[2.1-a]isoquinoline ring.

A further special subaspect (subaspect 13) of said aspects a and drefers to compounds of formula I according to aspects a and d, in which

-   R1 is 1-2C-alkoxy,-   R2 is hydrogen,-   R3 is 1-2C-alkoxy.

Compounds according to subaspect 13 more worthy to be mentioned arethose, in which R1 is bound to the 8-position and R3 is bound to the9-position of the pyrrolo[2.1-a]isoquinoline ring, or those, in which R1is bound to the 9-position and R3 is bound to the 8-position of thepyrrolo[2.1-a]isoquinoline ring.

A further special subaspect (subaspect 14) of said aspects a, b and drefers to compounds of formula I according to aspects a, b and d, inwhich

-   R1 is halogen,-   R2 is hydrogen,-   R3 is 1-2C-alkoxy,

Compounds according to subaspect 14 more worthy to be mentioned arethose, in which R1 is bound to the 8-position and R3 is bound to the9-position of the pyrrolo[2.1-a]isoquinoline ring, or those, in which R1is bound to the 9-position and R3 is bound to the 8-position of thepyrrolo[2.1-a]isoquinoline ring.

A further special subaspect (subaspect 15) of said aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R1 is halogen,-   R2 is 1-2C-alkoxy,-   R3 is 1-2C-alkoxy.

Compounds according to subaspect 15 more worthy to be mentioned arethose, in which none of R1, R2 and R3 is bound to the 10-position of thepyrrolo[2.1-a]isoquinoline ring.

A further special subaspect (subaspect 16) of said aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R1 is halogen,-   R2 is halogen,-   R3 is 1-2C-alkoxy.

Compounds according to subaspect 16 more worthy to be mentioned arethose, in which none of R1, R2 and R3 is bound to the 10-position of thepyrrolo[2.1-a]isoquinoline ring.

A further special subaspect (subaspect 17) of said aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R1 is halogen, nitro, 1-4C-alkyl or 1-4C-alkoxy-2-4C-alkoxy.

A further special subaspect (subaspect 18) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R1 is chlorine or fluorine.

Compounds according to subaspect 18 more worthy to be mentioned arethose, in which R1 is not bound to the 10-position of thepyrrolo[2.1-a]isoquinoline ring.

A further special subaspect (subaspect 19) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen.

A further special subaspect (subaspect 20) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen.

A further special subaspect (subaspect 21) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich either

-   R4 is 1-4C-alkyl, or-   R41 is 1-4C-alkyl.

A further special subaspect (subaspect 22) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R6 is 1-6C-alkyl, or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl.

A further special subaspect (subaspect 23) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R6 is methyl, ethyl or methoxycarbonylethyl.

A further special subaspect (subaspect 24) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R6 is methyl.

A further special subaspect (subaspect 25) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R6 is methoxycarbonylethyl.

A further special subaspect (subaspect 26) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R7 is Het2, R74- and/or R75-substituted Het2, or    hydroxy-dimethyl-phenyl, in which-   Het2 is pyridinyl or quinolinyl,-   R74 is halogen, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, cyano,    amino, mono- or di-1-4C-alkylamino, 1-4C-alkoxycarbonyl, carboxyl,    nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl.

Compounds according to subaspect 26 more worthy to be mentioned arethose, in which

-   R7 is Het2, R74 and/or R75-substituted Het2, or    4-hydroxy-3,5-dimethylphenyl, in which-   Het2 is pyridinyl or quinolinyl,-   R74 is halogen, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, cyano,    amino, mono- or di-1-4C-alkylamino, 1-4C-alkoxycarbonyl, carboxyl,    nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl.

A further special subaspect (subaspect 27) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R7 is pyridin-4-yl.

A further special subaspect (subaspect 28) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R7 is 2,6-dimethylpyridin-4-yl.

A further special subaspect (subaspect 29) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R7 is quinolin-4-yl.

A further special subaspect (subaspect 30) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R8 is phenyl, phenylcarbonyl or —C(O)—N(R82)R83, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,    3-7C-cycloalkyl-1-4C-alkyl, phenyl or phenyl-1-4C-alkyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl, piperidinyl, morpholinyl or    N-1-4C-alkyl)-piperazinyl.

A further special subaspect (subaspect 31) of aspects a, b, c and drefers to compounds of formula I according to aspects a, b, c and d, inwhich

-   R8 is phenyl, phenylcarbonyl or —C(O)—N(R82)R83, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a pyrrolidinyl ring.

Special subaspects more worthy to be mentioned are the subaspects 11,12, 15, 23, 24, 25, 26, 27, 28 and 29.

Compounds according to aspect a more worthy to be mentioned are those offormula I, in which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is hydrogen or 1-4C-alkoxy,-   R3 is hydrogen or 1-4C-alkoxy, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge and R3 is hydrogen,-   R4 is hydrogen or 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,    or-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, or naphthyl, in which-   Het2 is a heteroaryl radical selected from the group consisting of    furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,    benzothiophenyl and benzofuranyl,-   R71 is hydroxyl, halogen, nitro, trifluoromethyl, 1-4C-alkyl,    1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino,    1-4C-alkylsulphonylamino, tolylsulphonylamino or aryloxy, in which-   aryl is R711-substituted phenyl, in which-   R711 is halogen,-   R72 is 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,    1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl,-   R8 is phenyl, phenylcarbonyl or —C(O)—N(R82)R83, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl,-   R83 is hydrogen or 1-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl and piperidinyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect a further more worthy to be mentioned arethose of formula I, in

which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is hydrogen,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring, in particular, none of R1 and R2 is    bound to the 7- or 10-position of the pyrrolo[2.1-a]isoquinoline    ring,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, formyl, or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, or naphthyl, in which-   Het2 is a heteroaryl radical selected from the group consisting of    furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,    benzothiophenyl and benzofuranyl,-   R71 is hydroxyl, 1-4C-alkoxy, amino or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,    1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl,-   R8 is phenyl, phenylcarbonyl, or —C(O)—N(R82)R83, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl and piperidinyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Yet compounds according to aspect a further more worthy to be mentionedare those of formula I, in

which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is hydrogen,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring, in particular, none of R1 and R2 is    bound to the 7- or 10-position of the pyrrolo[2.1-a]isoquinoline    ring,-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, formyl, or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, or naphthyl, in which-   Het2 is a heteroaryl radical selected from the group consisting of    furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,    benzothiophenyl and benzofuranyl,-   R71 is hydroxyl, 1-4C-alkoxy, amino or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,    1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl,-   R8 is phenyl, phenylcarbonyl, or —C(O)—N(R82)R83, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl and piperidinyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect a in particular worthy to be mentioned arethose of formula I, in which

-   R1 is chlorine, fluorine, nitro, amino, methyl, methoxy,    methoxyethoxy or difluoromethoxy,-   R2 is hydrogen or methoxy,-   R3 is hydrogen or methoxy, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a difluoromethylenedioxy bridge and R3 is    hydrogen,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is hydrogen or methyl,-   R41 is hydrogen or methyl,-   R5 is hydrogen,-   R51 is hydrogen,    or-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is methyl, ethyl or methoxycarbonylethyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    or naphthyl, in which-   Het2 is indolyl, pyridinyl or quinolyl,-   R71 is hydroxyl, chlorine, methoxy, dimethylamino, or aryloxy, in    which-   aryl is R711-substituted phenyl, in which-   R711 is chlorine,-   R72 is methyl, tert-butyl or methoxy,-   R73 is methyl, tert-butyl or methoxy,-   R8 is phenyl, phenylcarbonyl or —C(O)—N(R82)R83, in which-   R82 is hydrogen, methyl, ethyl, iso-propyl, iso-butyl, cyclohexyl,    cyclopropyl or phenyl,-   R83 is hydrogen or methyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a pyrrolidinyl radical,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect a in further particular worthy to bementioned are those of formula I, in which

either

-   R1 is bonded in the 8-position of the pyrrolodihydroisoquinoline    scaffold, and is chlorine, methoxy, methoxyethoxy or    difluoromethoxy,-   R2 is bonded in the 9-position of the pyrrolodihydroisoquinoline    scaffold, and is methoxy,-   R3 is hydrogen,    or-   R1 is bonded in the 9-position of the pyrrolodihydroisoquinoline    scaffold, and is chlorine, fluorine, methoxy, nitro, methyl, amino,    or difluoromethoxy,-   R2 is bonded in the 8-position of the pyrrolodihydroisoquinoline    scaffold, and is methoxy,-   R3 is hydrogen,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is methyl, ethyl or methoxycarbonylethyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    or naphthyl, in which-   Het2 is indolyl, pyridinyl or quinolyl,-   R71 is hydroxyl, methoxy or dimethylamino, in which-   R72 is methyl, tert-butyl or methoxy,-   R73 is methyl, tert-butyl or methoxy,-   R8 is phenylcarbonyl, or —C(O)—N(R82)R83, in which-   R82 is hydrogen, methyl, ethyl, iso-propyl, iso-butyl, cyclohexyl,    cyclopropyl or phenyl,-   R83 is hydrogen or methyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a pyrrolidinyl radical,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Yet compounds according to aspect a in further particular worthy to bementioned are those of formula I, in which

either

-   R1 is bonded in the 8-position of the pyrrolodihydroisoquinoline    scaffold, and is chlorine, methoxy, methoxyethoxy or    difluoromethoxy,-   R2 is bonded in the 9-position of the pyrrolodihydroisoquinoline    scaffold, and is methoxy,-   R3 is hydrogen,    or-   R1 is bonded in the 9-position of the pyrrolodihydroisoquinoline    scaffold, and is chlorine, fluorine, methoxy, nitro, methyl, amino,    or difluoromethoxy,-   R2 is bonded in the 8-position of the pyrrolodihydroisoquinoline    scaffold, and is methoxy,-   R3 is hydrogen,-   R4 is methyl,-   R41 is hydrogen or methyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is methyl, ethyl or methoxycarbonylethyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    or naphthyl, in which-   Het2 is indolyl, pyridinyl or quinolyl,-   R71 is hydroxyl, methoxy or dimethylamino, in which-   R72 is methyl, tert-butyl or methoxy,-   R73 is methyl, tert-butyl or methoxy,-   R8 is phenylcarbonyl, or —C(O)—N(R82)R83, in which-   R82 is hydrogen, methyl, ethyl, iso-propyl, iso-butyl, cyclohexyl,    cyclopropyl or phenyl,-   R83 is hydrogen or methyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a pyrrolidinyl radical,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect b more worthy to be mentioned are those offormula I, in which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkoxy, or    completely or predominantly fluorine-substituted 1-4C-alkoxy,    with the provisio that R1 is not trifluoromethoxy,-   R2 is hydrogen or 1-4C-alkoxy,-   R3 is hydrogen or 1-4C-alkoxy, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge and R3 is hydrogen,-   R4 is hydrogen or 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,    or-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-4C-alkyl, formyl, or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, or naphthyl, in which-   Het2 is a heteroaryl radical selected from the group consisting of    furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,    benzothiophenyl and benzofuranyl,-   R71 is hydroxyl, halogen, nitro, trifluoromethyl, 1-4C-alkyl,    1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino,    1-4C-alkylsulphonylamino, tolylsulphonylamino or aryloxy, in which-   aryl is R711-substituted phenyl, in which-   R711 is halogen,-   R72 is 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,    1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl and piperidinyl,-   R9 is 1-4C-alkyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect b further more worthy to be mentioned arethose of formula I, in

which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkoxy, or    completely or predominantly fluorine-substituted 1-4C-alkoxy,    with the provisio that R1 is not trifluoromethoxy,-   R2 is 1-4C-alkoxy,-   R3 is hydrogen, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge and R3 is hydrogen,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring, in particular, none of R1 and R2 is    bound to the 7- or 10-position of the pyrrolo[2.1-a]isoquinoline    ring,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, formyl, or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, or naphthyl, in which-   Het2 is a heteroaryl radical selected from the group consisting of    furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,    benzothiophenyl and benzofuranyl,-   R71 is hydroxyl, 1-4C-alkoxy, amino or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,    1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or, in particular,    —C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl and piperidinyl,-   R9 is 1-4C-alkyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Yet compounds according to aspect b further more worthy to be mentionedare those of formula I, in

which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkoxy, or    completely or predominantly fluorine-substituted 1-4C-alkoxy,    with the provisio that R1 is not trifluoromethoxy,-   R2 is 1-4C-alkoxy,-   R3 is hydrogen, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge and R3 is hydrogen,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring, in particular, none of R1 and R2 is    bound to the 7- or 10-position of the pyrrolo[2.1-a]isoquinoline    ring,-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, formyl, or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, or naphthyl, in which-   Het2 is a heteroaryl radical selected from the group consisting of    furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,    benzothiophenyl and benzofuranyl,-   R71 is hydroxyl, 1-4C-alkoxy, amino or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,    1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or, in particular,    —C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl and piperidinyl,-   R9 is 1-4C-alkyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect b in particular worthy to be mentioned arethose of formula I, in which

-   R1 is chlorine, fluorine, nitro, amino, methyl, methoxyethoxy or    difluoromethoxy,-   R2 is hydrogen or methoxy,-   R3 is hydrogen or methoxy, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a difluoromethylenedioxy bridge and R3 is    hydrogen,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is hydrogen or methyl,-   R41 is hydrogen or methyl,-   R5 is hydrogen,-   R51 is hydrogen,    or-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is methyl, ethyl or methoxycarbonylethyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    or naphthyl, in which-   Het2 is indolyl, pyridinyl or quinolyl,-   R71 is hydroxyl, chlorine, methoxy, dimethylamino, or aryloxy, in    which-   aryl is R711-substituted phenyl, in which-   R711 is chlorine,-   R72 is methyl, tert-butyl or methoxy,-   R73 is methyl, tert-butyl or methoxy,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9, in which-   R82 is hydrogen, methyl, ethyl, iso-propyl, iso-butyl, cyclohexyl,    cyclopropyl or phenyl,-   R83 is hydrogen or methyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a pyrrolidinyl radical,-   R9 is methyl or ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect b in further particular worthy to bementioned are those of formula I, in which

either

-   R1 is bonded in the 8-position of the pyrrolodihydroisoquinoline    scaffold, and is chlorine, methoxyethoxy or difluoromethoxy,-   R2 is bonded in the 9-position of the pyrrolodihydroisoquinoline    scaffold, and is methoxy,-   R3 is hydrogen,    or-   R1 is bonded in the 9-position of the pyrrolodihydroisoquinoline    scaffold, and is chlorine, fluorine, nitro, methyl, amino, or    difluoromethoxy,-   R2 is bonded in the 8-position of the pyrrolodihydroisoquinoline    scaffold, and is methoxy,-   R3 is hydrogen,    or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a difluoromethylenedioxy bridge and R3 is    hydrogen,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R61 is hydrogen,-   R6 is methyl, ethyl or methoxycarbonylethyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    or naphthyl, in which-   Het2 is indolyl, pyridinyl or quinolyl,-   R71 is hydroxyl, methoxy or dimethylamino, in which-   R72 is methyl, tert-butyl or methoxy,-   R73 is methyl, tertbutyl or methoxy,-   R8 is phenylcarbonyl, —C(O)—N(R82)R83 or, in particular, —C(O)—OR9,    in which-   R82 is hydrogen, methyl, ethyl, iso-propyl, iso-butyl, cyclohexyl,    cyclopropyl or phenyl,-   R83 is hydrogen or methyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a pyrrolidinyl radical,-   R9 is methyl or ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Yet compounds according to aspect b in further particular worthy to bementioned are those of formula I, in which

either

-   R1 is bonded in the 8-position of the pyrrolodihydroisoquinoline    scaffold, and is chlorine, methoxyethoxy or difluoromethoxy,-   R2 is bonded in the 9-position of the pyrrolodihydroisoquinoline    scaffold, and is methoxy,-   R3 is hydrogen,    or-   R1 is bonded in the 9-position of the pyrrolodihydroisoquinoline    scaffold, and is chlorine, fluorine, nitro, methyl, amino, or    difluoromethoxy,-   R2 is bonded in the 8-position of the pyrrolodihydroisoquinoline    scaffold, and is methoxy,-   R3 is hydrogen,    or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a difluoromethylenedioxy bridge and R3 is    hydrogen,-   R4 is methyl,-   R41 is hydrogen or methyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is methyl, ethyl or methoxycarbonylethyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    or naphthyl, in which-   Het2 is indolyl, pyridinyl or quinolyl,-   R71 is hydroxyl, methoxy or dimethylamino, in which-   R72 is methyl, tert-butyl or methoxy,-   R73 is methyl, tert-butyl or methoxy,-   R8 is phenylcarbonyl, —C(O)—N(R82)R83 or, in particular, —C(O)—OR9,    in which-   R82 is hydrogen, methyl, ethyl, iso-propyl, iso-butyl, cyclohexyl,    cyclopropyl or phenyl,-   R83 is hydrogen or methyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a pyrrolidinyl radical,-   R9 is methyl or ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect c more worthy to be mentioned are those offormula I, in which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy,-   R4 is hydrogen or 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,    or-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, or naphthyl, in which-   Het2 is a heteroaryl radical selected from the group consisting of    furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,    benzothiophenyl and benzofuranyl,-   R71 is hydroxyl, halogen, nitro, trifluoromethyl, 1-4C-alkyl,    1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino,    1-4C-alkylsulphonylamino, tolylsulphonylamino or aryloxy, in which-   aryl is R711-substituted phenyl, in which-   R711 is halogen,-   R72 is 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,    1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl and piperidinyl,-   R9 is 1-4C-alkyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect c further more worthy to be mentioned arethose of formula I, in

which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy, and none of R1, R2 and R3 is bound to the    10-position of the pyrrolo[2.1-a]isoquinoline ring,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, formyl, or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, or naphthyl, in which-   Het2 is a heteroaryl radical selected from the group consisting of    furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,    benzothiophenyl and benzofuranyl,-   R71 is hydroxyl, 1-4C-alkoxy, amino or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,    1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or, in particular,    —C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl and piperidinyl,-   R9 is 1-4C-alkyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Yet compounds according to aspect c further more worthy to be mentionedare those of formula I, in

which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, formyl, or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, or naphthyl, in which-   Het2 is a heteroaryl radical selected from the group consisting of    furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,    benzothiophenyl and benzofuranyl,-   R71 is hydroxyl, 1-4C-alkoxy, amino or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,    1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or, in particular,    —C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl and piperidinyl,-   R9 is 1-4C-alkyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect c in particular worthy to be mentioned arethose of formula I, in which

-   R1 is chlorine, fluorine, nitro, amino, methyl, methoxy,    methoxyethoxy or difluoromethoxy,-   R2 is methoxy,-   R3 is methoxy,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is hydrogen or methyl,-   R41 is hydrogen or methyl,-   R5 is hydrogen,-   R51 is hydrogen,    or-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is methyl, ethyl or methoxycarbonylethyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    or naphthyl, in which-   Het2 is indolyl, pyridinyl or quinolyl,-   R71 is hydroxyl, chlorine, methoxy, dimethylamino, or aryloxy, in    which-   aryl is R711-substituted phenyl, in which-   R711 is chlorine,-   R72 is methyl, tert-butyl or methoxy,-   R73 is methyl, tert-butyl or methoxy,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9, in which-   R82 is hydrogen, methyl, ethyl, iso-propyl, iso-butyl, cyclohexyl,    cyclopropyl or phenyl,-   R83 is hydrogen or methyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a pyrrolidinyl radical,-   R9 is methyl or ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect d more worthy to be mentioned are those offormula I, in which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is hydrogen or 1-4C-alkoxy,-   R3 is hydrogen or 1-4C-alkoxy, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a completely or predominantly    fluorine-substituted 1-2C-alkylenedioxy bridge and R3 is hydrogen,-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, or naphthyl, in which-   Het2 is a heteroaryl radical selected from the group consisting of    furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,    benzothiophenyl and benzofuranyl,-   R71 is hydroxyl, halogen, nitro, trifluoromethyl, 1-4C-alkyl,    1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino,    1-4C-alkylsulphonylamino, tolylsulphonylamino or aryloxy, in which-   aryl is R711-substituted phenyl, in which-   R711 is halogen,-   R72 is 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,    1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl and piperidinyl,-   R9 is 1-4C-alkyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect d further more worthy to be mentioned arethose of formula I, in

which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is hydrogen,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring, in particular none of R1 and R2 is    bound to the 7- or 10-position of the pyrrolo[2.1-a]isoquinoline    ring,-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, formyl, or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    R74- and/or R75-substituted Het2, or naphthyl, in which-   Het2 is a heteroaryl radical selected from the group consisting of    furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,    benzothiophenyl and benzofuranyl,-   R71 is hydroxyl, 1-4C-alkoxy, amino or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 114 alkoxy,-   R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,    1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy,-   R75 is 1-4C-alkyl,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or, in particular,    —C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl,-   R83 is hydrogen or 1-4C-alkyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a heterocyclic ring radical selected from    the group consisting of pyrrolidinyl and piperidinyl,-   R9 is 1-4C-alkyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect d in particular worthy to be mentioned arethose of formula I, in which

-   R1 is chlorine, fluorine, nitro, amino, methyl, methoxy,    methoxyethoxy or difluoromethoxy,-   R2 is hydrogen or methoxy,-   R3 is hydrogen or methoxy, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form a difluoromethylenedioxy bridge and R3 is    hydrogen,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is methyl,-   R41 is hydrogen or methyl,-   R5 is hydrogen,-   R51 is hydrogen,    or-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is methyl,-   R51 is hydrogen,-   R6 is methyl, ethyl or methoxycarbonylethyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    or naphthyl, in which-   Het2 is a heteroaryl radical selected from the group consisting of    furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,    benzothiophenyl and benzofuranyl,-   R71 is hydroxyl, chlorine, methoxy, dimethylamino, or aryloxy, in    which-   aryl is R711-substituted phenyl, in which-   R711 is chlorine,-   R72 is methyl, tert-butyl or methoxy,-   R73 is methyl, tert-butyl or methoxy,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9, in which-   R82 is hydrogen, methyl, ethyl, iso-propyl, iso-butyl, cyclohexyl,    cyclopropyl or phenyl,-   R83 is hydrogen or methyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a pyrrolidinyl radical,-   R9 is methyl or ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Compounds according to aspect d in further particular worthy to bementioned are those of formula I, in which

either

-   R1 is bonded in the 8-position of the pyrrolodihydroisoquinoline    scaffold, and is chlorine, methoxy, methoxyethoxy or    difluoromethoxy,-   R2 is bonded in the 9-position of the pyrrolodihydroisoquinoline    scaffold, and is methoxy,-   R3 is hydrogen,    or-   R1 is bonded in the 9-position of the pyrrolodihydroisoquinoline    scaffold, and is chlorine, fluorine, methoxy, nitro, methyl, amino,    or difluoromethoxy,-   R2 is bonded in the 8-position of the pyrrolodihydroisoquinoline    scaffold, and is methoxy,-   R3 is hydrogen,-   R4 is methyl,-   R41 is hydrogen or methyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is methyl, ethyl or methoxycarbonylethyl,-   R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl,    or naphthyl, in which-   Het2 is indolyl, pyridinyl or quinolyl,-   R71 is hydroxyl, methoxy or dimethylamino, in which-   R72 is methyl, tert-butyl or methoxy,-   R73 is methyl, tert-butyl or methoxy,-   R8 is phenylcarbonyl, —C(O)—N(R82)R83 or, in particular, —C(O)—OR9,    in which-   R82 is hydrogen, methyl, ethyl, iso-propyl, iso-butyl, cyclohexyl,    cyclopropyl or phenyl,-   R83 is hydrogen or methyl, or-   R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bound, form a pyrrolidinyl radical,-   R9 is methyl or ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

A special interest of the compounds according to this invention refersto those compounds of formula I which are included, within the scope ofthis invention, by one or, when possible, by more of the followingembodiments:

A special embodiment (embodiment a) of the compounds according to thisinvention refers to those compounds of formula I, in which

-   R8 is —C(O)—OR9.

Another special embodiment (embodiment b) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R8 is phenylcarbonyl.

Another special embodiment (embodiment c) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R8 is phenyl.

Another special embodiment (embodiment d) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R8 is —C(O)—N(R82)R83.

Another special embodiment (embodiment e) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R4, R41, R5 and R51 are all hydrogen.

Another special embodiment (embodiment f) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R4 is 1-4C-alkyl, such as e.g. methyl,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen.

Another special embodiment (embodiment g) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R4 is 1-4C-alkyl, such as e.g. methyl,-   R41 is 1-4C-alkyl, such as e.g. methyl,-   R5 is hydrogen,-   R51 is hydrogen.

Another special embodiment (embodiment h) of the compounds according tothis invention refers to those compounds of formula I, in which

none of R1, R2 and R3 is bound to the 10-position of thepyrrolo[2.1-a]isoquinoline ring.

Another special embodiment (embodiment i) of the compounds according tothis invention refers to those compounds of formula I, in which

none of R1 and R2 is bound to the 7- or 10-position of thepyrrolo[2.1-a]isoquinoline ring, and

-   R3 is hydrogen.

Another special embodiment (embodiment J) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R1 is 1-4C-alkoxy, hydroxyl, 1-4C-alkoxy-2-4C-alkoxy,    3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or    -   completely or predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is halogen or 1-4C-alkoxy,-   R3 is hydrogen.

Another special embodiment (embodiment k) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R1 is 1-4C-alkoxy, hydroxyl, 1-4C-alkoxy-2-4C-alkoxy,    3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or    -   completely or predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is halogen or 1-4C-alkoxy,-   R3 is 1-4C-alkoxy.

Another special embodiment (embodiment l) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R1 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is hydrogen;    in particular-   R1 is 1-2C-alkoxy, 1-2C-alkoxy-ethoxy, or completely or    predominantly fluorine-substituted 1-2C-alkoxy,-   R2 is 1-2C-alkoxy,-   R3 is hydrogen.

Another special embodiment (embodiment m) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R1 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is halogen,-   R3 is hydrogen;    in particular-   R1 is 1-2C-alkoxy, 1-2C-alkoxy-ethoxy, or completely or    predominantly fluorine-substituted 1-2C-alkoxy,-   R2 is chlorine or fluorine,-   R3 is hydrogen;    in more particular-   R1 is 1-2C-alkoxy,-   R2 is chlorine or fluorine,-   R3 is hydrogen.

Another special embodiment (embodiment n) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is halogen or 1-4C-alkoxy,-   R3 is hydrogen.

Another special embodiment (embodiment o) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R1 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, or    completely or predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy.

Another special embodiment (embodiment p) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R1 is bonded in the 8-position of the pyrrolo[2.1-a]isoquinoline    ring, and is halogen, 1-4C-alkoxy-2-4C-alkoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is 1-4C-alkoxy,-   R3 is hydrogen.

Another special embodiment (embodiment q) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R1 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is halogen, nitro, methyl, amino, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is bonded in the 8-position of the pyrrolo[2.1-a]isoquinoline    ring, and is 1-4C-alkoxy,-   R3 is hydrogen.

Each and every group of compounds of formula I according to thisinvention, in which R1, R2 and R3 bonded to the left benzo ring of thedihydroisoquinoline moiety of the pyrrolo[2.1-a]isoquinoline ringconstitute any one of the substitution patterns as shown and specifiedin the following represents a respective further independent specialembodiment of the compounds according to this invention:

in which

-   either, in a first independent special embodiment,-   R′ is 1-2C-alkoxy, such as e.g. methoxy; and R″ is 1-2C-alkoxy, such    as e.g. methoxy;-   or, in a second independent special embodiment,-   R′ is 1-2C-alkoxy, such as e.g. methoxy; and R″ is difluoromethoxy;-   or, in a third independent special embodiment,-   R′ is chlorine; and R″ is 1-2C-alkoxy, such as e.g. methoxy;-   or, in a fourth independent special embodiment,-   R′ is 1-2C-alkoxy, such as e.g. methoxy; and R″ is chlorine;-   or, in a fifth independent special embodiment,-   R′ is 2-methoxy-ethoxy; and R″ is 1-2C-alkoxy, such as e.g. methoxy;-   or, in a sixth independent special embodiment,-   R′ is difluoromethoxy; and R″ is 1-2C-alkoxy, such as e.g. methoxy;-   or, in a seventh independent special embodiment,-   R′ is 1-2C-alkoxy, such as e.g. methoxy; and R″ is fluorine.

Another special embodiment (embodiment r) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R7 is naphthyl (such as e.g. naphthalen-1-yl),    4-hydroxy-3,5-dimethylphenyl, 3-dimethylamino-phenyl,    3,4,5-trimethoxy-phenyl, pyridinyl or quinolin-4-yl.

Another special embodiment (embodiment s) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R7 is 4-hydroxy-3,5-dimethylphenyl.

Another special embodiment (embodiment t) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R7 is 3-dimethylamino-phenyl.

Another special embodiment (embodiment u) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R7 is Het2, in which-   Het2 is a fused bicyclic 9- or 10-membered heteroaryl radical    comprising one to three heteroatoms, each of which is selected from    a group consisting of nitrogen, oxygen and sulfur, which optionally    contains a benzene ring,    -   such as e.g. quinolyl or indolyl.

Another special embodiment (embodiment v) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R6 is 1-4C-alkyl, such as e.g. methyl.

Another special embodiment (embodiment w) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R6 is 1-4C-alkyl substituted by 1-4C-alkoxycarbonyl, such as e.g.    2-methoxycarbonyl-ethyl.

Another special embodiment (embodiment x) of the compounds according tothis invention refers to those compounds of formula I, in which

-   R1 is halogen, amino, 1-4C-alkyl, 1-4C-alkoxy, hydroxyl,    1-4C-alkoxy-2-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy,    or completely or predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy,    and-   R4 is 1-4C-alkyl, such as e.g. methyl,-   R41 is hydrogen, or 1-4C-alkyl, such as e.g. methyl,-   R5 is hydrogen,-   R51 is hydrogen.

A notable embodiment of the compounds according to this invention refersto those compounds of formula I, in which

-   R1 is 1-4C-alkoxy,-   R2 is hydrogen or 1-4C-alkoxy,-   R3 is hydrogen, or-   R1 and R2 bound to the benzo ring moiety in ortho-position to each    other together form an 1-2C-alkylenedioxy bridge and R3 is hydrogen,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, or R61-substituted 1-4C-alkyl, particularly R6 is    methyl, in which-   R61 is 1-4C-alkoxycarbonyl,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, particularly ethyl.

Yet a notable embodiment of the compounds according to this inventionrefers to those compounds of formula I, in which

-   R1 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, or    completely or predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy, and none of R1, R2 and R3 is bound to the    10-position of the pyrrolo[2.1-a]isoquinoline ring,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, or R61-substituted 1-4C-alkyl, particularly R6 is    methyl, in which-   R61 is 1-4C-alkoxycarbonyl,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, particularly ethyl.

Still a notable embodiment of the compounds according to this inventionrefers to those compounds of formula I, in which

-   R1 is 1-4C-alkoxy-2-4C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is halogen,-   R3 is 1-4C-alkoxy,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, or R61-substituted 1-4C-alkyl, particularly R6 is    methyl, in which-   R61 is 1-4C-alkoxycarbonyl,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, particularly ethyl.

Still yet a notable embodiment of the compounds according to thisinvention refers to those compounds of formula I, in which R1 ishalogen,

-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, or R61-substituted 1-4C-alkyl, particularly R6 is    methyl, in which-   R61 is 1-4C-alkoxycarbonyl,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, particularly ethyl.

A further notable embodiment of the compounds according to thisinvention refers to those compounds of formula I, in which

-   R1 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, or    completely or predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-4C-alkyl, or R61-substituted 1-4C-alkyl, particularly R6 is    methyl, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is Het2, in which-   Het2 optionally contains a benzene ring, and is a fused bicyclic 9-    or 10-membered heteroaryl radical comprising one to three    heteroatoms, each of which is selected from a group consisting of    nitrogen, oxygen and sulfur,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, particularly ethyl.

Yet a further notable embodiment of the compounds according to thisinvention refers to those compounds of formula I, in which

-   R1 is 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is halogen,-   R3 is 1-4C-alkoxy,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-4C-alkyl, or R61-substituted 1-4C-alkyl, particularly R6 is    methyl, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is Het2, in which-   Het2 optionally contains a benzene ring, and is a fused bicyclic 9    or 10-membered heteroaryl radical comprising one to three    heteroatoms, each of which is selected from a group consisting of    nitrogen, oxygen and sulfur,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, particularly ethyl.

Another notable embodiment of the compounds according to this inventionrefers to those compounds of formula I, in which

-   R1 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, or    completely or predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2,1-a]isoquinoline ring,-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, or R61-substituted 1-4C-alkyl, particularly R6 is    methyl, in which-   R61 is 1-4C-alkoxycarbonyl,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, particularly ethyl.

Yet another notable embodiment of the compounds according to thisinvention refers to those compounds of formula I, in which

-   R1 is 1-4C-alkoxy-2-4C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is halogen,-   R3 is 1-4C-alkoxy,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, or R61-substituted 1-4C-alkyl, particularly R6 is    methyl, in which-   R61 is 1-4C-alkoxycarbonyl,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, particularly ethyl.

Still yet another notable embodiment of the compounds according to thisinvention refers to those compounds of formula I, in which

-   R1 is halogen,-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, or R61-substituted 1-4C-alkyl, particularly R6 is    methyl, in which-   R61 is 1-4C-alkoxycarbonyl,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, particularly ethyl.

Another further notable embodiment of the compounds according to thisinvention refers to those compounds of formula I, in which

-   R1 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, or    completely or predominantly fluorine-substituted 1-4C-alkoxy, —-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-4C-alkyl, or R61-substituted 1-4C-alkyl, particularly R6 is    methyl, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is Het2, in which-   Het2 optionally contains a benzene ring, and is a fused bicyclic 9-    or 10-membered heteroaryl radical comprising one to three    heteroatoms, each of which is selected from a group consisting of    nitrogen, oxygen and sulfur,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, particularly ethyl.

Yet another further notable embodiment of the compounds according tothis invention refers to those compounds of formula I, in which

-   R1 is 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is halogen,-   R3 is 1-4C-alkoxy,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-6C-alkyl, or R61-substituted 1-4C-alkyl, particularly R6 is    methyl, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is Het2, in which-   Het2 optionally contains a benzene ring, and is a fused bicyclic 9    or 10-membered heteroaryl radical comprising one to three    heteroatoms, each of which is selected from a group consisting of    nitrogen, oxygen and sulfur,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, particularly ethyl.

In a facet of this invention (facet 1), compounds according to thisinvention more worthy to be mentioned are those compounds of formula I,

in which, in a first embodiment,

either

-   R1 is halogen, 1-4C-alkyl, nitro, amino, 1-4C-alkoxy-2-4C-alkoxy, or    completely or predominantly fluorine-substituted 1-4C-alkoxy, and-   R2 is 1-4C-alkoxy,    or-   R1 is 1-4C-alkoxy, 1-4C-alkyl, nitro, amino,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy, and-   R2 is halogen,-   R3 is hydrogen,    either-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen, and-   R51 is hydrogen,    or-   R4 is 1-4C-alkyl,-   R41 is hydrogen or 1-4C-alkyl,-   R5 is hydrogen, and-   R51 is hydrogen;    or in which, in a second embodiment,-   R1 is 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is hydrogen,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen;-   R6 is 1-4C-alkyl, or 1-4C-alkyl substituted by R61, in which-   R61 is 1-4C-alkoxycarbonyl,-   R7 is Het2, R71- and/or R72- and/or R73-substituted phenyl, or    naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5- to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, 1-4C-alkoxy or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83, or, in particular,    —C(O)—OR9, in which-   R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, or phenyl,-   R83 is hydrogen, 1-4C-alkyl,-   or R82 and R83 together and with inclusion of the nitrogen atom, to    which they are bonded form a pyrrolidinyl or piperidinyl ring,-   R9 is 1-4C-alkyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 1 of this invention, compounds according tothis invention in particular worthy to be mentioned are those compoundsof formula I, in which

either

-   R1 is chlorine, fluorine, 1-2C-alkyl, nitro, amino,    1-2C-alkoxy-ethoxy, or completely or predominantly    fluorine-substituted 1-2C-alkoxy, and-   R2 is 1-2C-alkoxy,    or-   R1 is 1-2C-alkoxy, 1-2C-alkyl, nitro, amino, 1-2C-alkoxy-ethoxy, or    completely or predominantly fluorine-substituted 1-2C-alkoxy, and-   R2 is halogen,-   R3 is hydrogen,    and none of R1 and R2 is bound to the 7- or 10-position of the    pyrrolo[2.1-a]isoquinoline ring,    either-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen, and-   R51 is hydrogen,    or-   R4 is i-2C-alkyl,-   R41 is hydrogen or 1-2C-alkyl,-   R5 is hydrogen, and-   R51 is hydrogen,-   R6 is 1-2C-alkyl, or 1-2C-alkyl substituted by R61, in which-   R61 is 1-2C-alkoxycarbonyl,-   R7 is naphthyl (such as e.g. naphthalen-1-yl),    4-hydroxy-3,5-dimethylphenyl, 3-dimethylamino-phenyl or quinolinyl,-   R8 is —C(O)—OR9, in which-   R9 is 1-2C-alkyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 1 of this invention, yet compoundsaccording to this invention in particular worthy to be mentioned arethose compounds of formula I, in which

-   R1 is 1-2C-alkoxy,-   R2 is 1-2C-alkoxy,-   R3 is hydrogen,    and none of R1 and R2 is bound to the 7- or 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is 1-2C-alkyl,-   R41 is hydrogen or 1-2C-alkyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-2C-alkyl, or 1-2C-alkyl substituted by R61, in which-   R61 is 1-2C-alkoxycarbonyl,-   R7 is naphthyl (such as e.g. naphthalen-1-yl),    4-hydroxy-3,5-dimethylphenyl, 3-dimethylamino-phenyl or quinolinyl,-   R8 is —C(O)—OR9, in which-   R9 is 1-2C-alkyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 1 of this invention, compounds according tothis invention in more particular worthy to be mentioned are thosecompounds of formula I, in which

either

-   R1 is bonded in the 8-position of the pyrrolo[2.1-a]isoquinoline    ring, and is chlorine, 2-methoxy-ethoxy or difluoromethoxy, and R2    is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline ring,    and is 1-2C-alkoxy,    or-   R1 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is chlorine, fluorine, nitro, methyl, amino or    difluoromethoxy, and-   R2 is bonded in the 8-position of the pyrrolo[2.1-a]isoquinoline    ring, and is 1-2C-alkoxy,-   R3 is hydrogen;-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is methyl or 2-methoxycarbonylethyl;-   R7 is naphthyl (such as e.g. naphthalen-1-yl),    4-hydroxy-3,5-dimethylphenyl, 3-dimethylamino-phenyl or    quinolin-4-yl;-   R8 is —C(O)—OR9, in which-   R9 is 1-2C-alkyl;    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 1 of this invention, yet compoundsaccording to this invention in more particular worthy to be mentionedare those compounds of formula I, in which

-   R1 is bonded in the 8-position of the pyrrolo[2.1-a]isoquinoline    ring, and is methoxy,-   R2 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is methoxy,-   R3 is hydrogen;-   R4 is methyl,-   R41 is methyl or hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is methyl or 2-methoxycarbonylethyl;-   R7 is naphthyl (such as e.g. naphthalen-1-yl),    4-hydroxy-3,5-dimethylphenyl, 3-dimethylamino-phenyl or quinolinyl;-   R8 is —C(O)—OR9, in which-   R9 is 1-2C-alkyl;    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 1 of this invention, compounds according tothis invention in further more particular worthy to be mentioned arethose compounds of formula I, in which

either

-   R1 is bonded in the 8-position of the pyrrolo[2.1-a]isoquinoline    ring, and is chlorine, 2-methoxy-ethoxy or difluoromethoxy, and-   R2 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is 1-2C-alkoxy,    or-   R1 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is chlorine, fluorine or difluoromethoxy, and-   R2 is bonded in the 8-position of the pyrrolo[2.1-a]isoquinoline    ring, and is 1-2C-alkoxy,-   R3 is hydrogen;    either-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen, and-   R51 is hydrogen,    or-   R4 is methyl,-   R41 is hydrogen or methyl,-   R5 is hydrogen, and-   R51 is hydrogen;-   R6 is methyl;-   R7 is 4-hydroxy-3,5-dimethylphenyl or 3-dimethylamino-phenyl;-   R8 is —C(O)—OR9, in which-   R9 is ethyl;    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 1 of this invention, yet compoundsaccording to this invention in further more particular worthy to bementioned are those compounds of formula I, in which

-   R1 is bonded in the 8-position of the pyrrolo[2.1-a]isoquinoline    ring, and is methoxy,-   R2 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is methoxy,-   R3 is hydrogen;-   R4 is methyl,-   R41 is hydrogen or methyl,-   R5 is hydrogen,-   R51 is hydrogen;-   R6 is methyl;-   R7 is 4-hydroxy-3,5-dimethylphenyl or 3-dimethylamino-phenyl;-   R8 is —C(O)—OR9, in which-   R9 is ethyl;    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 1 of this invention, compounds according tothis invention in still further more particular worthy to be mentionedare those compounds of formula I, in which

either

-   R1 is bonded in the 8-position of the pyrrolo[2.1-a]isoquinoline    ring, and is chlorine, 2-methoxy-ethoxy or difluoromethoxy, and-   R2 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is methoxy,    or-   R1 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is chlorine, fluorine or difluoromethoxy, and-   R2 is bonded in the 8-position of the pyrrolo[2.1-a]isoquinoline    ring, and is methoxy,-   R3 is hydrogen;    either-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen, and-   R51 is hydrogen,    or-   R4 is methyl,-   R41 is hydrogen or methyl,-   R5 is hydrogen, and-   R51 is hydrogen;-   R6 is methyl;-   R7 is naphthalen-1-yl, 4-hydroxy-3,5-dimethylphenyl,    3-dimethylamino-phenyl or quinolin-4-yl;-   R8 is —C(O)—OR9, in which-   R9 is ethyl;    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 1 of this invention, yet compoundsaccording to this invention in still further more particular worthy tobe mentioned are those compounds of formula I, in which

-   R1 is bonded in the 8-position of the pyrrolo[2.1-a]isoquinoline    ring, and is methoxy,-   R2 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is methoxy,-   R3 is hydrogen;-   R4 is methyl,-   R41 is hydrogen or methyl,-   R5 is hydrogen,-   R51 is hydrogen;-   R6 is methyl;-   R7 is naphthalen-1-yl, 4-hydroxy-3,5-dimethylphenyl,    3-dimethylamino-phenyl or quinolin-4-yl;-   R8 is C(O)—OR9, in which-   R9 is ethyl;    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

In another facet of this invention (facet 2), compounds according tothis invention more worthy to be mentioned are those compounds offormula I,

-   R1 is 1-4C-alkoxy, such as e.g. methoxy,-   R2 is 1-4C-alkoxy, such as e.g. methoxy,-   R3 is hydrogen,    and none of R1 and R2 is bound to the 7- or 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is 1-4C-alkyl, such as e.g. methyl,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-4C-alkyl, such as e.g. methyl,-   R7 is Het2, R71- and/or R72- and/or R73-substituted phenyl, or    naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5- to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, 1-4C-alkoxy or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-allyl, such as e.g. ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 2 of this invention, other compoundsaccording to this invention more worthy to be mentioned are thosecompounds of formula I,

-   R1 is 1-4C-alkoxy, such as e.g. methoxy,-   R2 is 1-4C-alkoxy, such as e.g. methoxy,-   R3 is hydrogen,    and none of R1 and R2 is bound to the 7- or 10-position of the    pyrrolo[2.1-a]isoquinoline ring,-   R4 is 1-4C-alkyl, such as e.g. methyl,-   R41 is 1-4C-alkyl, such as e.g. methyl,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-4C-alkyl, such as e.g. methyl,-   R7 is Het2, R71- and/or R72- and/or R73-substituted phenyl, or    naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5- to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, 1-4C-alkoxy or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, such as e.g. ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 2 of this invention, other compoundsaccording to this invention more worthy to be mentioned are thosecompounds of formula I,

-   R1 is bonded in the position of the pyrrolo[2.1-a]isoquinoline ring,    and is difluoromethoxy,-   R2 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is methoxy,-   R3 is hydrogen,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-4C-alkyl, such as e.g. methyl,-   R7 is Het2, R71- and/or R72- and/or R73-substituted phenyl, or    naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5- to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, 1-4C-alkoxy or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, such as e.g. ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 2 of this invention, other compoundsaccording to this invention more worthy to be mentioned are thosecompounds of formula I,

-   R1 is bonded in the position of the pyrrolo[2.1-a]isoquinoline ring,    and is methoxy,-   R2 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is difluoromethoxy,-   R3 is hydrogen,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-4C-alkyl, such as e.g. methyl,-   R7 is Het2, R71- and/or R72- and/or R73-substituted phenyl, or    naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5- to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, 1-4C-alkoxy or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, such as e.g. ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 2 of this invention, other compoundsaccording to this invention more worthy to be mentioned are thosecompounds of formula I,

-   R1 is bonded in the 8-position of the pyrrolo[2.1-a]isoquinoline    ring, and is 1-4C-alkoxy-2-4C-alkoxy, such as e.g. 2-methoxyethoxy,-   R2 is bonded in the 9-position of the pyrrolo[2.1-a]isoquinoline    ring, and is methoxy,-   R3 is hydrogen,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-4C-alkyl, such as e.g. methyl,-   R7 is Het2, R71- and/or R72- and/or R73-substituted phenyl, or    naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5- to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, 1-4C-alkoxy or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, such as e.g. ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 2 of this invention, other compoundsaccording to this invention more worthy to be mentioned are thosecompounds of formula I,

-   R1 is halogen,-   R2 is hydrogen,-   R3 is 1-2C-alkoxy,    particularly-   R1 is bound to the 8-position and R3 is bound to the 9-position of    the pyrrolo[2.1-a]isoquinoline ring, or-   R1 is bound to the 9-position and R3 is bound to the 8-position of    the pyrrolo[2.1-a]isoquinoline ring,-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen,-   R6 is 1-4C-alkyl, such as e.g. methyl,-   R7 is Het2, R71- and/or R72- and/or R73-substituted phenyl, or    naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5- to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, 1-4C-alkoxy or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, such as e.g. ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

In yet another facet of this invention (facet 3), compounds according tothis invention more worthy to be mentioned are those compounds offormula I,

either

-   R1 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, 1-4C-alkoxy-2-4C-alkoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy, and-   R3 is 1-4C-alkoxy,    or-   R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is halogen, and-   R3 is 1-4C-alkoxy;-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen;-   R6 is 1-4C-alkyl;-   R7 is Het2, R71- and/or R72- and/or R73-substituted phenyl, or    naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5- to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R71 is hydroxyl, 1-4C-alkoxy or mono- or di-1-4C-alkylamino,-   R72 is 1-4C-alkyl or 1-4C-alkoxy,-   R73 is 1-4C-alkyl or 1-4C-alkoxy,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, such as e.g. ethyl.    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 3 of this invention, compounds according tothis invention in particular worthy to be mentioned are those compoundsof formula I,

either

-   R1 is chlorine, fluorine, 1-4C-alkyl, 1-4C-alkoxy, 3-5C-cycloalkoxy,    3-5C-cycloalkylmethoxy, 1-4C-alkoxy-2-4C-alkoxy, or completely or    predominantly fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy, and-   R3 is 1-4C-alkoxy,    or-   R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is chlorine or fluorine, and-   R3 is 1-4C-alkoxy,    and none of R1, R2 and R3 is bound to the 10-position of the    pyrrolo[2.1-a]isoquinoline ring;-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen;-   R6 is 1-4C-alkyl, such as e.g. methyl;-   R7 is Het2,4-hydroxy-3,5-dimethylphenyl, 3-dimethylamino-phenyl, or    naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5- to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, such as e.g. ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

Also in the meaning of facet 3 of this invention, compounds according tothis invention in more particular worthy to be mentioned are thosecompounds of formula I,

-   R1 is chlorine, fluorine, 1-4C-alkyl, 1-4C-alkoxy,    1-4C-alkoxy-2-4C-alkoxy, or completely or predominantly    fluorine-substituted 1-4C-alkoxy,-   R2 is 1-4C-alkoxy,-   R3 is 1-4C-alkoxy, and none of R1, R2 and R3 is bound to the    10-position of the pyrrolo[2.1-a]isoquinoline ring;-   R4 is hydrogen,-   R41 is hydrogen,-   R5 is hydrogen,-   R51 is hydrogen;-   R6 is 1-4C-alkyl, such as e.g. methyl;-   R7 is Het2,4-hydroxy-3,5-dimethylphenyl, 3-dimethylamino-phenyl, or    naphthyl, in which-   Het2 is a monocyclic or fused bicyclic 5- to 10-membered heteroaryl    radical comprising one to three heteroatoms, each of which is    selected from a group consisting of nitrogen, oxygen and sulfur,-   R8 is —C(O)—OR9, in which-   R9 is 1-4C-alkyl, such as e.g. ethyl,    and the salts, stereoisomers, hydrates and hydrates of the salts of    these compounds.

As exemplary compounds according to this invention may be mentioned anycompound selected from the group consisting of:

-   1.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3,5,6-trimethyl-5,6-dihydro-pyrrolo[2,1-α]isoquinoline-1-carboxylic    acid ethyl ester,-   2.    (6RS)-2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3,6-dimethyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   3.    (6RS)-8,9-Dimethoxy-3,6-dimethyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   4.    9-(1,1-Difluoro-methoxy)-2-(3-dimethylamino-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   5.    9-(1,1-Difluoro-methoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   6.    9-(1,1-Difluoro-methoxy)-8-methoxy-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   7.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9,10-trimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   8.    8-(1,1-Difluoro-methoxy)-9-methoxy-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   9.    8-(1,1-Difluoro-methoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-9-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   10.    8-(1,1-Difluoro-methoxy)-2-(3-dimethylamino-phenyl)-9-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   11.    8,9-(1,1-Difluoro-methylenedioxy)-2-(3-dimethylamino-phenyl)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   12.    8,9-(1,1-Difluoro-methylenedioxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   13.    8,9-(1,1-Difluoro-methylenedioxy)-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   14.    9-Chloro-2-(4-hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   15.    9-Chloro-8-methoxy-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   16.    9-Chloro-2-(3-dimethylamino-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   17.    8-Chloro-2-(4-hydroxy-3,5-dimethyl-phenyl-9-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   18.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-9-methoxy-8-(2-methoxy-ethoxy)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   19.    9-Methoxy-8-(2-methoxy-ethoxy)-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   20.    9-Methoxy-8-(2-methoxy-ethoxy-3-methyl-2-naphthalen-1-yl-5,6-dihydro-pyrrolo[2.1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   21.    9-Fluoro-2-(4-hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   22.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-9-nitro-5,6-dihydro-pyrroio[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   23.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-methoxy-3,9-dimethyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   24.    8,9-Dimethoxy-3-(2-methoxycarbonyl-ethyl)-6,6-dimethyl-2-quinolin-yl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   25.    9-Amino-2-(4-hydroxy-3,5-dimethyl-phenyl)ethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethyl ester,-   26.    1-[2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrralo[2,1-a]isoquinolin-1-yl-1-phenyl-methanone,-   27.    4-(8,9-Dimethoxy-3-methyl-1-phenyl-5,6-dihydro-pyrrolo[2,1-a]isoquinolin-2-yl)-2,6-dimethyl-phenol,-   28.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid cyclohexyl amide,-   29.    1-[2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinolin-1-yl]-1-pyrrollidin-1-yl-methanone,-   30.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid isopropylamide,-   31.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid dimethylamide,-   32.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid dimethylamide,-   33.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid amide,-   34.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid phenylamide,-   35.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid ethylamide,-   36.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]]isoquinoline-1-carboxylic    acid sec-butylamide, and-   37.    2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic    acid cyclopropylamide;    whereby as a more interesting exemplary compound according to this    invention may be mentioned any compound selected from the group    consisting of the following compounds specified by means of their    Example numbers: 1, 2, 4, 5, 9, 10, 16, 18, 20, 21, 22, 25, 28, 30,    34 and 36; or the salts, stereoisomers, hydrates or hydrates of the    salts thereof;

The compounds according to the present invention can be prepared, forexample, in an art-known manner, or in a manner described and shown asfollows, or as disclosed in WO 02/48144, WO 03/014115, WO 03/014116, WO03/014117 or WO 03/051877, or as described byway of example in thefollowing examples, or analogously or similarly thereto.

As shown in the scheme above, in a first reaction step compounds offormula VIII, in which R1, R2, R3, R4, R41, R5 and R51 have the meaningsindicated above, are reacted with compounds of formula VII, in which R8has the meanings indicated above and L is a suitable leaving group, forexample chlorine or an acycloxy radical (e.g. the R8-CH₂—C(O)O—radical), to give in the presence of a suitable organic or inorganicbase corresponding compounds of formula VI.

Alternatively, compounds of formula VI are also accessible fromcompounds of formula VIII, in which R1, R2, R3, R4, R41, R5 and R51 havethe meanings indicated above, and compounds of formula VII, in which R8has the meanings indicated above and L is hydroxyl, by reaction withamide bond linking reagents known to the person skilled in the art.Exemplary amide bond linking reagents known to the person skilled in theart which may be mentioned are, for example, the carbodiimides (e.g.dicyclohexylcarbodiimide or, preferably,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride),azodicarboxylic acid derivatives (e.g. diethyl azodicarboxylate),uronium salts [e.g. 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramthyl-uronium-hexafluorophosphate]and N,N′-carbonyldiimidazole. In the scope of this invention preferredamide bond linking reagents are uronium salts and, particularly,carbodiimides, preferably, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride.

Said reactions are carried out under conditions known to the personskilled in the art or as described exemplarily in the followingexamples.

As shown in the next step, compounds of the formula IV, in which R1, R2,R3, R4, R41, R5, R51 and R8 have the meanings indicated above, can beobtained by cyclocondensation of corresponding compounds of the formulaVI. Said cyclocondensation reaction is carried out in a manner habitualper se to the person skilled in the art or as described by way ofexample in the following examples, according to Bischler-Napieralski(e.g. as described in J. Chem. Soc., 1958, 4280-4282) in the presence ofa suitable condensing or dehydrating agent, such as, for example,polyphosphoric add, phosphorus pentachloride, phosphorus pentoxide orphosphorus oxychloride, in a suitable inert solvent, e.g. in achlorinated hydrocarbon such as chloroform, or in a cyclic hydrocarbonsuch as toluene or xylene, or another inert solvent such asacetonitrile, or without further solvent using an excess of condensingagent, at reduced temperature, or at room temperature, or at elevatedtemperature or at the boiling temperature of the solvent or condensingagent used.

Compounds of formula IV are converted either with compounds of formulaeII, in which R7 has the meanings given above, and III, in which R6 is1-6C-alkyl or 1-4C-alkyl substituted by 1-4C-alkoxycarbonyl, or withcompounds of formula V, in which R7 has the meanings given above and R6is 1-6C-alkyl or 1-4C-alkyl substituted by 1-4C-alkoxycarbonyl,optionally in a one pot synthesis and suitably in the presence of aninorganic or organic base (in particular a cyclic amine, e.g.piperidine) into the corresponding compounds of formula I.

Said conversion can be carried out as known to the skilled person or asdescribed in the following examples or analogously or similarly thereto.

Compounds of formulae VIII, VII, III and II are commercially availableor can be obtained in a manner known to the skilled person from his/herexpert knowledge and/or from literature.

Compounds of formula V are known or are accessible by reaction ofcompounds of formula II with compounds of formula III in the presence ofa suitable organic or inorganic base in a manner customary per se to theskilled person.

Compounds of formula I obtained can be converted into further compoundsof formula I by methods known to one of ordinary skill in the art. Morespecifically, for example, from compounds of the formula I, in which

-   -   a.) R8, R61, R71, R74 or R76 are an ester group, the        corresponding adds can be obtained by acidic or, particularly,        alkaline hydrolysis;    -   b.) R8 is an ester or carboxyl group, the corresponding amides        can be obtained by amidification reactions;    -   c.) R6 is 1-4C-alkyl, particularly methyl, the corresponding        halogenated, preferably chlorinated, groups can be obtained by        halogenation reaction, particularly by reaction with a        chlorination reagent such as sulfuryl chloride, thionyl chloride        or N-chlorosuccinimide;    -   d.) R6 is 1-4C-alkyl substituted by halogen, the corresponding        derivatized 1-4C-alkyl radicals substituted by 1-4C-alkoxy,        hydroxyl, halogen or —N(R611)R612 can be obtained by        nucleophilic substitution reactions with suitable nucleophiles;    -   e.) R6 is 1-4C-alkyl substituted by hydroxyl, the corresponding        derivatized 1-4C-alkyl radicals substituted by        1-4C-alkoxycarbonyl can be obtained by oxidation and        esterification reactions under suitable conditions;    -   f.) R6 is methyl, the corresponding oxidized forms thereof (e.g.        the hydroxymethyl or formyl radicals) can be obtained stepwise        or directly by selective oxidation reactions (e.g. with the aid        of manganese dioxide to obtain the formyl radicals);    -   g.) R6 is formyl, the corresponding aminated compounds can be        obtained by reductive amination reaction;    -   h.) R6 is hydroxymethyl, the corresponding fluorine compounds        can be obtained by fluorination reaction;    -   i.) R6 is methyl, the corresponding amino compounds can be        obtained by nitration reaction and subsequential reduction of        the nitro compounds obtained.

The methods mentioned under a.) to i.) are expediently carried outanalogously to the methods known to the person skilled in the art or asdescribed by way of example in the following examples. It is moreoverknown to the person skilled in the art that if there are a number ofreactive centers on a starting or intermediate compound it may benecessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in“Protective Groups in Organic Synthesis” by T. Greene and P. Wuts (JohnWiley & Sons, Inc. 1999, 3^(rd) Ed.) or in “Protecting Groups (ThiemeFoundations Organic Chemistry Series N Group” by P. Kocienski (ThiemeMedical Publishers, 2000).

The isolation and purification of the substances according to theinvention is carried out in a manner known per se, e.g. by distillingoff the solvent in vacuo and recrystallizing the resulting residue froma suitable solvent or subjecting it to one of the customary purificationmethods, such as, for example, column chromatography on suitable supportmaterial.

Salts are obtained by dissolving the free compound in a suitable solvent(e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutylketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, achlorinated hydrocarbon, such as methylene chloride or chloroform, or alow molecular weight aliphatic alcohol such as ethanol or isopropanol)which contains the desired acid or base, or to which the desired acid orbase is then added. The salts are obtained by filtering,reprecipitating, precipitating with a nonsolvent for the addition saltor by evaporating the solvent. Salts obtained can be converted byalkalization or by acidification into the free compounds, which in turncan be converted into salts. In this way, pharmacologically intolerablesalts can be converted into pharmacologically tolerable salts.

The person skilled in the art knows on the basis of his/her knowledgeand on the basis of those synthesis mutes, which are shown and describedwithin the description of this invention, how to find other possiblesynthesis routes for compounds of the formula I. All these otherpossible synthesis routes are also part of this invention.

Having described the invention in detail, the scope of the presentinvention is not limited only to those described characteristics orembodiments. As will be apparent to persons skilled in the art,modifications, variations and adaptations to the described invention canbe made on the base of the disclosure (e.g. the explicite, implicite orinherent disclosure) of the present invention without departing from thespirit and scope of this invention.

The following examples serve to illustrate the invention in greaterdetail without restricting it. Likewise, further compounds of theformula I, whose preparation is not explicitly described, can also beprepared in an analogous manner or in a manner familiar per se to theperson skilled in the art using customary process techniques.

In the examples, m.p. stands for melting point, h for hour(s), min forminutes, conc. for concentrated, said. for saturated, MS for massspectrum, M for molecular ion.

The compounds mentioned in the examples as well as their salts andstereoisomers are a preferred subject of the invention.

EXAMPLES

Final Products

1.2-(4-Hydroxy-3,5-dimethyl-phenyl-8,9-dimethoxy-3,5,6-trimethyl-5,6-dihydro-pyrrolo[2,1-a]isoquinolin-1-carboxylicacid ethyl ester

Analogously to a procedure described by Meyer in Liebigs Ann. Chem.1981, 9, 1534-1544,(6,7-dimethoxy-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-ylidene)-aceticacid ethyl ester (compound A8) is reacted with nitro ethane and4-hydroxy-3,5-dimethyl benzaldehyde to afford2-(4-hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3,6,6-trimethyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester as a colorless solid of m.p. 200-202° C. The massspectrum shows the molecular peak M+H at 464.3 Da.

The following examples (Examples 2-24) can be prepared in analogy toexample 1 using the appropriate starting compound selected from thegroup consisting of the compounds A1 to A14. All aldehydes used arecommercially available or can be prepared in analogy to publishedprocedures. If nitro propane or 4-nitro butyric acid methyl ester isused instead of nitroethane,3-ethyl-5,6-dihydro-pyrollo[2,1-a]isoquinolines and3-(8,9-dimethoxy-5,6-dihydro-pyrrolo[2,1-a]isoquinolin-3-yl)propionicmethyl esters, respectively are obtained.

2.(6RS)-2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3,6-dimethyl-5,6-dihydro-prrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=450.1; m.p.=191-194° C.

3.(6RS)-8,9-Dimethoxy-3,6-dimethyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrroio[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=496.0; m.p.=150° C.

4.9-(1,1-Difluoro-methoxy)-2-(3-dimethylamino-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=470.8; m.p.=107-110° C.

5.9-(1,1-Difluoro-methoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=471.8; m.p.=152-155° C.

6. 9-(1,1-Difluoro-methoxy-methoxy-methyl-2-(3,4,5-trimethoxy-phenyl)5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylic acid ethyl ester

MS (M+H)=517.8; m.p.=138-141° C.

7.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9,10-trimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=466.1; m.p.=246-251° C.

8.8-(1,1-Difluoro-methoxy)-9-methoxy-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=517.7; m.p.=155° C.

9.8-(1,1-Difluoro-methoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-9-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=471.7; m.p.=126-128° C.

10.8-(1,1-Difluoro-methoxy)-2-(dimethylamino-phenyl)-9-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=470.7; m.p.=118-120° C.

11.8,9-(1,1-Difluoro-methylenedioxy)-2-(3-dimethylamino-phenyl)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=454.8; m.p.=136-139° C.

12.8,9-(1,1-Difluoro-methylenedioxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=455.6; m.p.=176-180° C.

13.8,9-(1,1-Difluoro-methylenedioxy)-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=501.7; m.p.=138-141° C.

14.9-Chloro-2-(4-hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrroio[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=470.7; m.p.=118-120° C.

15.9-Chloro-8-methoxy-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=485.6; m.p.=172-174° C.

16.9-Chloro-2-(3-dimethylamino-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1caboxylic acid ethyl ester

MS (M+H)=438.9; m.p.=133-135° C.

17.8-Chloro-2-(4-hydroxy-3,5-dimethyl-phenyl)-9-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=439.7; m.p.=167-169° C.

18.2-(4-Hydroxy-3,5-dimethyl-phenyl)-9-methoxy-8-(2-methoxy-ethoxy)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=480.2; m.p.=169-171° C.

19.9-Methoxy-8-(2-methoxy-ethoxy)-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=526.0; m.p.=152-154° C.

20.9-Methoxy-8-(2-methoxy-ethoxy)-3-methyl-2-naphthalen-1-yl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=486.2; m.p.=126-128° C.

21.9-Fluoro-2-(4-hydroxy-3,5-dimethyl-phenyl-ethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=423.6; m.p.=180-182° C.

22.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-9-nitro-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=450.7; m.p.=209-211° C.

23.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3,9-dimethyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=420.0; m.p.=179-181° C.

24.8,9-Dimethoxy-3-(2-methoxycarbonyl-ethyl)-6,6-dimethyl-2-quinolin-4-yl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

MS (M+H)=543.4; oil

25.9-Amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester

A suspension of 200 mg (4.43 mmol) of2-(4-hydroxy-3,5-dimethyl-phenyl)-8-methoxy-9-nitro-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester (Example 22) and 100 mg of Pd/C (10%) catalyst in 30 mlof ethanol is placed into an apparatus parr. The bottle is filled withhydrogen at an initial pressure of 30 psi and shaked during 3 hours. Thesolution is filtered on celite and washed with ethanol and ethylacetate. After evaporation of the solvents, the residue is purified bychromatography on silica gel eluting with ethyl acetate/petroleum spirit(5:5) to afford 110 mg (59%) of the title compound as a beige solid ofm.p. 104-106° C. The mass spectrum shows the molecular peak M+H at 420.8Da.

26.1-[2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinolin-1-yl]-1-phenyl-methanone

Analogously to the procedure described for Example1,2-(6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-ylidene)-1-phenyl-ethanone(compound A13) is reacted with nitro ethane and 4-hydroxy-3,5-dimethylbenzaldehyde to afford1-[2-(4-hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinolin-1-yl]-1-phenyl-methanoneas a colorless solid of m.p. 194-196° C. The mass spectrum shows themolecular peak M+H at 467.6 Da.

27.4-(8,9-Dimethoxy-3-methyl-1-phenyl-5,6-dihydro-pyrrolo[2,1-a]isoquinolin-2-yl)-2,6-dimethyl-phenol

Analogously to the procedure described for Example1,1-benzylidene-6,7-dimethoxy-1,2,3,4 tetrahydro-isoquinoline (compoundA14) is reacted with nitro ethane and 4-hydroxy-3,5-dimethylbenzaldehyde to afford4-(8,9-dimethoxy-3-methyl-1-phenyl-5,6-dihydro-pyrrolo[2,1-a]isoquinolin-2-yl)-2,6-dimethyl-phenolas a colorless solid of m.p. 210-214° C. The mass spectrum shows themolecular peak M+H at 439.6 Da.

28.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid cyclohexyl amide

To a solution of 190 μl (1.65 mmol) of cyclohexyl amine in 2 ml oftoluene at 0° C. is added dropwise 970 μl (1.92 mmol) of a 2.0 Mtrimethylaluminum solution in toluene. The reaction mixture is stirredat room temperature for 1 hour and a solution of 240 mg (550 μmol) of2-(4-hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester (Example 1) dissolved in 4 ml of tetrahydrofurane and 2ml of toluene is added dropwise. The resulting mixture is stirred in asealed tube at 110° C. for 16 hours (reaction followed by TLC analysis).The reaction mixture is cooled to room temperature and 5 N aqueoussodium hydroxide solution is added slowly. The mixture is diluted withwater and extracted twice with ethyl acetate. The combined organicphases are dried over magnesium sulfate and concentrated. The residue ispurified by chromatography on silica gel eluting with ethylacetate/petroleum spirit (5:5) and then with ethyl acetate to afford 110mg (41%) of the title compound as a white solid of m.p. 273-276° C. Themass spectrum shows the molecular peak M+H at 488.6 Da.

The following examples (Examples 29-37) can be prepared in analogy toExample 28. All amines used are commercially available. If ammoniachloride is used instead of cyclohexyl amine, the free amide isobtained.

-   29.    1-[2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethyl-5,6-dihydro-pyrrolo[2,1-a]isoquinolin-1-yl]-pyrrollidin-1-yl-methanone

MS (M+H)=460.6; m.p.=216-218° C.

30.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydpyrrolo[2,1-a]isoquinoline-1-carboxylicacid isopropylamide

MS (M+H)=448.9; m.p.=233-235° C.

31.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid dimethylamide

MS (M+H)=434.5; m.p.=259-261° C.

32.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid methylamide

MS (M+H)=421.3; m.p.=281-283° C.

33.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid amide

MS (M+H)=407.2; m.p.=229-231° C.

34.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid phenylamide

MS (M+H)=482.6; m.p.=271-273° C.

35.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethylamide

MS (M+H)=435.9; m.p.=242-244° C.

36.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid sec-butylamide

MS (M+H)=464; m.p.=238-240° C.

37.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid cyclopropylamide

MS (M+H)=448.1; m.p.=254-256° C.

Starting Compounds

A1[7-Methoxy-6-(2-methoxy-ethoxy)-3,4-dihydro-2H-isoquinolin-1-ylidene)-aceticacid ethyl ester

The title compound can be obtained by a Bischler-Napieralski reaction(Ber. 1893, 26, 1903) usingN-{2-[4-methoxy-3-(2-methoxy-ethoxy)phenyl]-ethyl}-malonamic acid ethylester (compound B1) as the starting material.

MS (M+H)=237.2; m.p.=79-81° C.

The following 3,4-Dihydro-1-(2H)-isoquinolinylidene-derivatives A2 toA13 can be prepared according an analogous procedure using theappropriate starting compound selected from the group consisting of thecompounds B2 to B13:

-   A2    (7-Difluoromethoxy-6-methoxy-3,4-dihydro-2H-isoquinolin-1-ylidene)-acetic    acid ethyl ester-   A3    (6-Difluoromethoxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-ylidene)-acetic    acid ethyl ester-   A4    (2,2-Difluoro-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquinolin-5-ylidene)-acetic    acid ethyl ester-   A5 (7-Chloro-6-methoxy-3,4-dihydro-2H-isoquinolin-1-ylidene)-acetic    acid ethyl ester-   A6 (6-Chloro-7-methoxy-3,4-dihydro-2H-isoquinolin-1-ylidene)-acetic    acid ethyl ester-   A7    (4RS)-(6,7-Dimethoxy-4-methyl-3,4-dihydro-2H-isoquinolin-1-ylidene)-acetic    acid ethyl ester-   A8    (6,7-Dimethoxy-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-ylidene)-acetic    acid ethyl ester-   A9 (6,7,8-Trimethoxy-3,4-dihydro-2H-isoquinolin-1-ylidene)-acetic    acid ethyl ester-   A10 (6-Methoxy-7-methyl-3,4-dihydro-2H-isoquinolin-1-ylidene)-acetic    acid ethyl ester-   A11 (6-Methoxy-7-nitro-3,4-dihydro-2H-isoquinolin-1-ylidene)-acetic    acid ethyl ester-   A12 (7-Fluoromethoxy-3,4-dihydro-2H-isoquinolin-1-ylidene)-acetic    acid ethyl ester-   A13    2-(6,7-Dimethoxy-3,4-dihydro-2H-isoquinolin-1-ylidene)-1-phenyl-ethanone

The compound A13 can be prepared analogously to the above-describedsynthesis of compound A1 using the starting compound B13.

-   A14 1-Benzylidene-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

The compound A14 is commercially available.

B1 N-{2-[4-methoxy-3-(2-methoxy-ethoxy)-phenyl]-ethyl}-malonamic acidethyl ester

N{2-[4-methoxy-3-(2-methoxy-ethoxy)-phenyl]-ethyl}-malonamic acid ethylester can be prepared by a reaction of2-[4-Methoxy-3-(2-methoxy-ethoxy)-phenyl)-ethylamine (compound C1) withethyl maloyl chloride in analogy to procedures in the literature (e.g.Benovsky et al., Tetrahedron Lett. 1997, 38, 8475-8478).

MS (M+H)=3402; m.p.=70° C.

The following amides B2 to B12 can be synthesized according an analogousprocedure:

-   B2 N-{2-[4-(1,1-Difluoro-methoxy)-3-methoxy-phenyl]-ethyl}malonamic    acid ethyl ester-   B3 N-{2-[3-(1,1-Difluoro-methoxy)-4-methoxy-phenyl]-ethyl}-malonamic    acid ethyl ester-   B4 N-[2-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-ethyl]-malonamic acid    ethyl ester-   B5 N-[2-(4Chloro-3-methoxy-phenyl)-ethyl]-malonamic acid ethyl ester-   B6 N-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-malonamic acid ethyl    ester-   B7 N-[(RS)-2-(3,4-Dimethoxy-phenyl)-propyl]-malonamic acid ethyl    ester-   B8 N-[2-(3,4-Dimethoxy-phenyl)-2-methyl-propyl]-malonamic acid ethyl    ester-   B9 N-[2-(3,4,5-Trimethoxy-phenyl)-ethyl]-malonamic acid ethyl ester-   B10 N-[2-(3-Methoxy-4-methyl-phenylkthyl]-malonamic acid ethyl ester-   B11 N-[2-(3-Methoxy-4-nitro-phenyl)-ethyl]-malonamic acid ethyl    ester-   B12 N-[2-(4-Fluoro-3-methoxy-phenyl)-ethyl]-malonamic acid ethyl    ester-   B13 N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-oxo-3-phenyl-propionamide

To a solution of 1.10 g (6.07 mmol) of2-(3,4-dimethoxy-phenyl)-ethylamine in toluene (6 mL) at 0° C. is addeddropwise 3.78 mL (7.57 mmol) of a trimethylaluminum 2.0 M solution intoluene. The reaction mixture is stirred at room temperature during 1hour and a solution of 0.53 mL (3.03 mmol) of ethyl benzoylacetate intoluene (4 ml) is added dropwise. The resulting mixture is stirred in asealed tube at 100° C. during 16 hours (reaction followed by TLCanalysis). The reaction mixture is cooled to room temperature and 5 Naqueous solution of sodium hydroxide is slowly added. The mixture isdiluted with water and extracted twice with ethyl acetate. The combinedorganic phases are dried over magnesium sulfate and concentrated. Theresidue is purified by chromatography on silica gel eluting with ethylacetate to afford 680 mg (68%) of the title compound as a yellow oil. MS(M+H)=227.7

The appropriate starting compounds for the preparation of the compoundsB1 to B13 are commercially available, or can be prepared as describedbelow in the synthesis of the compounds C1 to C3 or analogously orsimilarly thereto, or can be obtained in analogy to publishedprocedures, e.g. the substituted 2-phenethyl amines can be preparedstarling from the corresponding benzaldehydes (see also Shepard et al.,J. Org. Chem. 1952, 17, 568).

C1 2-[4-Methoxy-3-(2-methoxy-ethoxy)-phenyl]-ethylamine

2-[4-Methoxy-3-(2-methoxy-ethoxy)-phenyl]-ethylamine can be prepared byalkylation of 4-methoxy-3-hydroxy benzaldehyde with 2-bromomethyl ethylether (analogous to a procedure by Ashton et al., J. Med. Chem. 1994,37, 1696-1703), followed by a sequence described by Shepard et al. in J.Org. Chem. 1952, 17, 568.

MS (M+H)=226.0

C2 2-[4-(1,1-Difluoro-methoxy)-3-methoxy-phenyl]-ethylamine

2-[4-(1,1-Difluoro-methoxy)-3-methoxy-phenyl]-ethylamine can be preparedby difluoromethylation of 4-hydroxy-3-methoxy benzaldehyde with chlorodifluoro methane according to a procedure published by Amschler et al.(WO97/28131), followed by a sequence described by Shepard et al. in J.Org. Chem. 1952, 17, 568.

MS (M+H)=217.6

C3 3-[4-(1,1-Difluoro-methoxy)-2-methoxy-phenyl]-ethylamine

3-[4-(1,1-Difluoro-methoxy)-2-methoxy-phenyl]-ethylamine was prepared bydifluoromethylation of 3-hydroxy-4-methoxy benzaldehyde with chlorodifluoro methane according to a procedure published by Amschler et al.(WO97/28131), followed by a sequence described by Shepard et al. in J.Org. Chem. 1952, 17, 568.

MS (M+H)=217.7

Commercial Utility

Commercial Applicability

The compounds according to the invention have miscellaneous valuablepharmacological properties which make them commercially utilizable.

The compounds according to the invention therefore can be employed astherapeutic agents for the treatment and prophylaxis of diseases inhuman and veterinary medicine.

Various diseases are caused by limitless replicative potential andaberrant cell proliferation (“hyperproliferation”) as well as evasionfrom apoptosis. These diseases include benign hypoplasia like that ofthe prostate (“BPH”) or colon epithelium. Most importantly thesediseases include malignant neoplasias commonly described as cancer andcharacterized by tumor cells finally metastasizing into distinct organsor tissues. Malignant neoplasia include solid and hematological tumors.Solid tumors are exemplified by tumors of the breast, bladder, bone,brain, central and peripheral nervus system, colon, endocrine glands (egthyroid and adrenal cortex), esophagus, endometrium, germ cells, headand neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma,sarcoma, ovary, pancreas, prostate, rectum, renal, small intestine, softtissue, testis, stomach, skin, ureter, vagina and vulva. Malignantneoplasias include inherited cancers exemplified by retinoblastoma andWilms tumor. In addition, malignant neoplasia include primary tumors insaid organs and corresponding secondary tumors in distant organs (“tumormetastases”). Hematological tumors are exemplified by aggressive andindolent forms of leukemia and lymphoma, namely non-Hodgkins disease,chronic and acute myeloid leukemia (CML/AML), acute lymphoblasticleukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma.Also included are myelodysplastic syndrome, plasma cell neoplasia,paraneoplastic syndromes, cancers of unknown primary site as well asAIDS related malignancies.

Compounds according to the present invention will commerciallyapplicable for treatment of the diseases of benign and malignantbehavior as described before, such as e.g. cancer.

Neoplastic cell proliferation might effect normal cell behaviour andorgan function. For example the formation of new blood vessels, aprocess described as neovascularization, is induced by tumors or tumormetastases. Compounds according to this invention will commerciallyapplicable for treatment of pathophysiological relevant processes causedby benign or neoplastic cell proliferation, such as but not limited toneovascularization by unphysiological proliferation of vascularendothelial cells.

Drug resistance is of particular importance for the frequent failure ofstandard cancer therapeutics. This drug resistance is caused by variouscellular and molelcular mechanisms like overexpression of drug effluxpumps or mutation within the cellular target protein. The commercialapplicability of the compounds according to this invention is notlimited to 1^(st) line treatment of patients. Patients with resistanceto defined cancer chemotherapeutics or target specific anti-cancer drugs(2^(nd) or 3^(rd) line treatment) are also amenable for treatment withthe compounds according to this invention.

In a facet of the present invention, the expression “cancer” includessolid tumors as well as leukemia, lymphoma and myeloma. Among solidtumors, preferred indications are malignancies of the lung, breast,pancreas, brain, prostate and ovar. Within this facet, the inventionrelates to a method for treating mammals, including humans, which/whoare suffering from cancer. The method is characterized by the fact thata therapeutically effective and pharmacologically tolerated quantity ofone or more of the compounds according to the invention is administeredto the affected mammal.

In another facet of the present invention, the compounds according tothis invention show interesting properties, which may make them usefulin the therapy of T-cell associated diseases, for suppression of theimmune system, for treating restenosis and/or, if appropriate, formodulating angiogenesis.

The invention further includes a method for treating hyperproliferativediseases and/or disorders responsive to the induction of apoptosis,particularly those diseases, disorders, conditions or illnessesmentioned above, in mammals, including humans, suffering therefromcomprising administering to said mammals in need thereof apharmacologically active and therapeutically effective and tolerableamount of one or more of the compounds according to this invention.

The present invention further includes a therapeutic method useful tomodulate apoptosis in vivo or aberrant cell growth in benign ormalignant neoplastic diseases, such as e.g. cancer, comprisingadministering to a subject in need of such therapy a therapeuticallyactive and pharmacologically effective and tolerable amount of one ormore of the compounds according to this invention which function byarresting aberrant cell growth and/or inducing apoptosis.

The present invention further relates to the use of the compoundsaccording to this invention for the production of pharmaceuticalcompositions which are employed for the treatment, prophylaxis and/oramelioration of the illnesses mentioned.

The present invention further relates to the use of the compoundsaccording to this invention for the production of pharmaceuticalcompositions which can be used in the treatment, prevention oramelioration of hyperproliferative diseases of benign or malignantbehaviour and/or disorders responsive to the induction of apoptosis in amammal, such as e.g. cancer.

The present invention further relates to the use of the compoundsaccording to this invention for the production of pharmaceuticalcompositions which can be used use in the treatment, prevention oramelioration of disorders responsive to arresting of aberrant cellgrowth and/or induction of apoptosis.

The present invention further relates to pharmaceutical compositionscomprising one or more of the compounds according to this invention anda pharmaceutically acceptable carrier or diluent.

The present invention further relates to combinations comprising one ormore of the compounds according to this invention and pharmaceuticallyacceptable auxiliaries, excipients or vehicles, e.g. for use in thetreatment, prevention or amelioration of hyperproliferative diseases ofbenign or malignant behaviour and/or disorders responsive to theinduction of apoptosis in a mammal, such as e.g. cancer.

The present invention further relates to a composition consistingessentially of a therapeutically effective and tolerable amount of oneor more pyrrolodihydroisoquinoline compounds according to this inventiontogether with the usual pharmaceutically acceptable vehicles, diluentsand/or excipients for use in therapy, e.g. for treating, preventing orameliorating hyperproliferative diseases, such as e.g. cancer, and/ordisorders responsive to induction of apoptosis.

The present invention further relates to compounds according to thisinvention for use in therapy, such as, for example, in the treatment,prevention or amelioration of those diseases mentioned herein, such ase.g. hyperproliferative diseases of benign or malignant behaviour and/ordisorders responsive to the induction of apoptosis, particularly cancer.

The present invention further relates to compounds according to thisinvention having anti-proliferative and/or apoptosis inducing activity.

The invention further relates to the use of a pharmaceutical compositioncomprising one or more of the compounds according to this invention assole active ingredient(s) and a pharmaceutically acceptable carrier ordiluent in the manufacture of pharmaceutical products for the treatmentand/or prophylaxis of the illnesses mentioned above.

The pharmaceutical compositions according to this invention are preparedby processes which are known per se and familiar to the person skilledin the art. As pharmaceutical compositions, the compounds of theinvention (=active compounds) are either employed as such, or preferablyin combination with suitable pharmaceutical auxiliaries and/orexcipients, e.g. in the form of tablets, coated tablets, capsules,caplets, suppositories, patches (e.g. as TTS), emulsions, suspensions,gels or solutions, the active compound content advantageously beingbetween 0.1 and 95% and where, by the appropriate choice of theauxiliaries and/or excipients, a pharmaceutical administration form(e.g. a delayed release form or an enteric form) exactly suited to theactive compound and/or to the desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries, vehicles,excipients, diluents, carriers or adjuvants which are suitable for thedesired pharmaceutical formulations, preparations or compositions onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound excipients, forexample antioxidants, dispersants, emulsifiers, preservatives,solubilizers, colorants, complexing agents or permeation promoters, canbe used.

Depending upon the particular disease, to be treated or prevented,additional therapeutic active agents, which are normally administered totreat or prevent that disease, may optionally be coadministered with thecompounds according to this invention. As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease are known as appropriate

for the disease being treated. For example, the compounds according tothis invention may be combined with one or more known anti-cancerchemotherapeutic agents and/or with other target specific anti-canceragents as described below.

Examples of known chemotherapeutic anti-cancer agents frequently usedfor combination therapy include, but not are limited to (i)alkylating/carbamylating agents such as Cyclophosphamid (Endoxan®),ifosfamid (Holoxan®), Thiotepa (Thiotehpa Lederle®), Melphalan(Alkeran®), or chloroethylnitrosourea (BCNU); (ii) platinum derivativeslike cis-platin (Platinex® BMS), oxaliplafin or carboplatin (Cabroplat®BMS); (iii) antimitotic agents/tubulin inhibitors such as vincaalkaloids (vincristine, vinblastine, vinorelbine), taxanes such as Taxol(Paclitaxel®), Taxotere (Docetaxel®) and analogs as well as newformulations and conjugates thereof; (iv) topoisomerase inhibitors suchas anthracyclines such as Doxorubicin (Adriblastin®),epipodophyllotoxines (such as Etoposide (Etopophos®) and camptothecinanalogs such as Topotecan (Hycamtin®); (v) pyrimidine antagonists suchas 5-fluorouracil (5-FU), Capecitabine (Xeloda®),Arabinosylcytosine/Cytarabin (Alexan®) or Gemcitabine (Gemzar®); (vi)purin antagonists such as 6-mercaptopurine (Puri-Nethol®), 6-thioguanineor fludarabine (Fludara®) and finally (vii) folic acid antagonists suchas methotrexate (Farmitrexat®).

Examples of target specific anti-cancer drug classes used inexperimental or standard cancer therapy include but are not limited to(i) kinase inhibitors such as e.g. Glivec (Imatinib®), ZD-1839/Iressa(Gefitinib®) or OSI-774/Tarceva (Erlotinib®); (ii) proteasome inhibitorssuch as PS-341 (Velcade®); (iii) histone deacetylase inhibitors likeSAHA, MS275, CI-994, Depsipeptide/FK228, LAQ-824 and butyrates; (iv)heat shock protein inhibitors like 17-allylaminogeldanamycin (17-AAG);(v) vascular targeting agents (VAT) like combretastatin A4 phosphate andanti-angiogenic drugs in general; (v) monoclonal antibodies such asHerceptin (Trastuzumab®) or MabThera/Rituxan (Rituximab®) and conjugatesof monoclonal antibodies and antibody fragments; (vi) oligonucleotidebased therapeutics like G-3139/Genasense (Oblimersen®); (vii) proteaseinhibitors (viii) hormonal therapeutics such as anti-estrogens (e.g.Tamoxifen), anti-androgens (e.g. Flutamide or Casodex), LHRH analogs(e.g. Leuprolide, Goserelin or Triptorelin) and aromatase inhibitors.

Other known anti-cancer agents which can be used for combination therapyinclude bleomycin, retinoids such as all-trans retinoic acid (ATRA), DNAmethyltransferase inhibitors such as the 2-deoxycytidine derivativeDecitabine (Docagen®), alanosine, cytokines such as interleukin-2 orinterferons such as interferon α2 or interferon-γ.

As exemplary chemotherapeutic/anti-cancer agents for use in thecombination therapy according to the present invention the followingdrugs may be mentioned, without being restricted thereto, 5 FU,actinomycin D, ABARELIX, ABCIXIMAB, ACLARUBICIN, ADAPALENE, ALEMTUZUMAB,ALTRETAMINE, AMINOGLUTETHIMIDE, AMIPRILOSE, AMRUBICIN, ANASTROZOLE,ANCITABINE, ARTEMISININ, AZATHIOPRINE, BASILIXIMAB, BENDAMUSTINE,BICALUTAMIDE, BLEOMYCIN, BROXURIDINE, BUSULFAN, CAPECITABINE,CARBOPLATIN, CARBOQUONE, CARMUSTINE, CETRORELIX, CHLORAMBUCIL,CHLORMETHINE, CISPLATIN, CLADRIBINE, CLOMIFENE, CYCLOPHOSPHAMIDE,DACARBAZINE, DACLIZUMAB, DACTINOMYCIN, DAUNORUBICIN, DESLORELIN,DEXRAZOXANE, DOCETAXEL, DOXIFLURIDINE, DOXORUBICIN, DROLOXIFENE,DROSTANOLONE, EDELFOSINE, EFLORNITHINE, EMITEFUR, EPIRUBICIN,EPITIOSTANOL, EPTAPLATIN, ERBITUX, ESTRAMUSTINE, ETOPOSIDE, EXEMESTANE,FADROZOLE, FINASTERIDE, FLOXURIDINE, FLUCYTOSINE, FLUDARABINE,FLUOROURACIL, FLUTAMIDE, FORMESTANE, FOSCARNET, FOSFESTROL, FOTEMUSTINE,FULVESTRANT, GEFITINIB, GEMCITABINE, GLIVEC, GOSERELIN, GUSPERIMUS,HERCEPTIN, IDARUBICIN, IDOXURIDINE, IFOSFAMIDE, IMATINIB, IMPROSULFAN,INFLIXIMAB, IRINOTECAN, LANREOTIDE, LETROZOLE, LEUPRORELIN, LOBAPLATIN,LOMUSTINE, MELPHALAN, MERCAPTOPURINE, METHOTREXATE, METUREDEPA,MIBOPLATIN, MIFEPRISTONE, MILTEFOSINE, MIRIMOSTIM, MITOGUAZONE,MITOLACTOL, MITOMYCIN, MITOXANTRONE, MIZORIBINE, MOTEXAFIN,NARTOGRASTIM, NEBAZUMAB, NEDAPLATIN, NILUTAMIDE, NIMUSTINE, OCTREOTIDE,ORMELOXIFENE, OXALIPLATIN, PACLITAXEL, PALIVIZUMAB, PEGASPARGASE,PEGFILGRASTIM, PENTETREOTIDE, PENTOSTATIN, PERFOSFAMIDE, PIPOSULFAN,PIRARUBICIN, PLICAMYCIN, PREDNIMUSTINE, PROCARBAZINE, PROPAGERMANIUM,PROSPIDIUM CHLORIDE, RALTITREXED, RANIMUSTINE, RANPIRNASE, RASBURICASE,RAZOXANE, RITUXIMAB, RIFAMPICIN, RITROSULFAN, ROMURTIDE, RUBOXISTAURIN,SARGRAMOSTIM, SATRAPLATIN, SIROLIMUS, SOBUZOXANE, SPIROMUSTINE,STREPTOZOCIN, TAMOXIFEN, TASONERMIN, TEGAFUR, TEMOPORFIN, TEMOZOLOMIDE,TENIPOSIDE, TESTOLACTONE, THIOTEPA, THYMALFASIN, TIAMIPRINE, TOPOTECAN,TOREMIFENE, TRASTUZUMAB, TREOSULFAN, TRIAZIQUONE, TRIMETREXATE,TRIPTORELIN, TROFOSFAMIDE, UREDEPA, VALRUBICIN, VERTEPORFIN,VINBLASTINE, VINCRISTINE, VINDESINE, VINORELBINE and VOROZOLE.

The person skilled in the art is aware on the base of his/her expertknowledge of the total daily dosage(s) of the additional therapeuticagent(s) coadministered. Said total daily dosage(s) can vary within awide range.

In a facet of the present invention, examples of known anti-canceragents include, but are not limited to, Gleevec, Herceptin, Rituxan,Adriamycin, Vincristine, Cyclophosphamide and ifosfamide,5-Fluorouracil, Topotecan, Doxorubicin, Paclitaxel Craxol), interferons,and Platinum derivatives like Cisplatin or Oxaliplatin.

In practicing the present invention, the compounds according to thisinvention may be administered in combination therapy separately,sequentially, simultaneously or chronologically staggered (such as e.g.as combined unit dosage forms, as separate unit dosage forms, asadjacent discrete unit dosage forms, as fixed or non-fixed combinations,as kit-of-parts or as admixtures) with one or more known anti-canceragents or target specific anti-cancer agents, such as e.g. thosementioned above.

In this context, the present invention further relates to a combinationcomprising

a first active ingredient, which is at least onepyrrolodihydroisoquinoline compound according to this invention, and

a second active ingredient, which is at least one anti-cancer agent ortarget specific anti-cancer agent, such as e.g. one or more of thosementioned herein above,

for separate, sequential, simultaneous or chronologically staggered usein therapy, such as e.g. to treat, prevent or amelioratehyperproliferative diseases of benign or malignant behaviour and/ordisorders responsive to the induction of apoptosis in a mammal, such ase.g. those diseases mentioned herein, for example cancer.

The term ‘combination’ according to this invention may be present as afixed combination, a non-fixed combination or a kit-of-parts.

A “fixed combination” is defined as a combination wherein the said firstactive ingredient and the said second active ingredient are presenttogether in one unit dosage or in a single entity. One example of a“fixed combination” is a pharmaceutical composition wherein the saidfirst active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A “kit-of-parts” is defined as a combination wherein the said firstactive ingredient and the said second active ingredient are present inmore than one unit. One example of a “kit-of-parts” is a combinationwherein the said first active ingredient and the said second activeingredient are present separately. The components of the kit-of-partsmay be administered separately, sequentially, simultaneously orchronologically staggered.

The present invention further relates to a pharmaceutical compositioncomprising

a first active ingredient, which is at least onepyrrolodihydroisoquinoline compound according to this invention, and

a second active ingredient, which is at least one anti-cancer agent ortarget specific anti-cancer agent, such as e.g. one or more of thosementioned herein above, and, optionally,

a pharmaceutically acceptable carrier or diluent,

for separate, sequential, simultaneous or chronologically staggered usein therapy.

The present invention further relates to a kit-of-parts comprising apreparation of a first active ingredient, which is apyrrolodihydroisoquinoline compound according to this invention, and apharmaceutically acceptable carrier or diluent; a preparation of asecond active ingredient, which is an art-known anti-cancer and/ortarget specific anti-cancer agent, such as one of those mentioned above,and a pharmaceutically acceptable carrier or diluent; for simultaneous,sequential, separate or chronologically staggered use in therapy.Optionally, said kit comprises instructions for its use in therapy, e.g.to treat hyperproliferative diseases and/or disorders responsive to theinduction of apoptosis, such as e.g. cancer.

The present invention further relates to a combined preparationcomprising at least one compound according to the present invention andat least one anti-cancer and/or target specific anticancer agent forsimultaneous, sequential or separate administration.

The present invention further relates to pharmaceutical combinations orcompositions according to this invention having anti-proliferativeand/or apoptosis inducing activity.

In addition, the present invention further relates to a method fortreating hyperproliferative diseases and/or disorders responsive to theinduction of apoptosis, such as e.g. cancer, in a patient comprisingadministering a combination, composition, formulation, preparation orkit as described herein to said patient in need thereof.

In addition, the present invention further relates to a method fortreating hyperproliferative diseases of benign or malignant behaviourand/or disorders responsive to the induction of apoptosis, such as e.g.cancer, in a patient comprising administering in combination therapyseparately, simultaneously, sequentially or chronologically staggered apharmaceutically active and therapeutically effective and tolerableamount of a pharmaceutical composition, which comprises apyrrolodihydroisoquinoline compound according to this invention and apharmaceutically acceptable carrier or diluent, and a pharmaceuticallyactive and therapeutically effective and tolerable amount of one or moreanti-cancer and/or target specific anti-cancer agents, such as e.g. oneor more of those mentioned herein, to said patient in need thereof.

In addition, the present invention further relates to the use of acomposition, combination, formulation, preparation or kit in themanufacture of a pharmaceutical product, such as e.g. a commercialpackage or a medicament, for treating, preventing or amelioratinghyperproliferative diseases, such as e.g. cancer, and/or disordersresponsive to the induction of apoptosis, particularly those diseasesmentioned herein.

The present invention further relates to a commercial package comprisingone or more compounds of the present invention together withinstructions for simultaneous, sequential or separate use with one ormore chemotherapeutic and/or target specific anti-cancer agents, such ase.g. any of those mentioned herein.

The present invention further relates to a commercial package consistingessentially of one or more compounds of the present invention as soleactive ingredient together with instructions for simultaneous,sequential or separate use with one or more chemotherapeutic and/ortarget specific anti-cancer agents, such as e.g. any of those mentionedherein.

The present invention further relates to a commercial package comprisingone or more chemotherapeutic and/or target specific anti-cancer agents,such as e.g. any of those mentioned herein, together with instructionsfor simultaneous, sequential or separate use with one or morepyrrolodihydroisoquinoline compounds according to the present invention.

The compositions, combinations, preparations, formulations, kits orpackages mentioned in the context of the combination therapy accordingto this invention may also include more than one of the compoundsaccording to this invention and/or more than one of the art-knownanti-cancer and/or target specific anticancer agents mentioned.

In addition, compounds according to the present invention can be used inthe pre- or post-surgical treatment of cancer.

In further addition, compounds of the present invention can be used incombination with radiation therapy.

A combination according to this invention can refer to a compositioncomprising both the compounds according to this invention and the otheractive anti-cancer agent in a fixed combination (fixed unit dosageform), or a medicament pack comprising the two active ingredients asdiscrete separate dosage forms (non-fixed combination). In case of amedicament pack comprising the two active ingredients, the activeingredients are preferably packed into blister cards which are suitedfor improving compliance.

Each blister card preferably contains the medicaments to be taken on oneday of treatment. If the medicaments are to be taken at different timesof day, the medicaments can be disposed in different sections on theblister card according to the different ranges of times of day at whichthe medicaments are to be taken (for example morning and evening ormorning, midday and evening). The blister cavities for the medicamentsto be taken together at a particular time of day are accommodated in therespective range of times of day. The various times of day are, ofcourse, also put on the blister in a dearly visible way. It is alsopossible, of course, for example to indicate a period in which themedicaments are to be taken, for example stating the times.

The daily sections may represent one line of the blister card, and thetimes of day are then identified in chronological sequence in thiscolumn.

Medicaments which must be taken together at a particular time of day areplaced together at the appropriate time on the blister card, preferablya narrow distance apart, allowing them to be pushed out of the blistereasily, and having the effect that removal of the dosage form from theblister is not forgotten.

The administration of the pharmaceutical compositions or combinationsaccording to the invention may be performed in any of the generallyaccepted modes of administration available in the art illustrativeexamples of suitable modes of administration include intravenous, oral,nasal, parenteral, topical, transdermal and rectal delivery. Oral andintravenous delivery are preferred.

For the treatment of dermatoses, the compounds of the invention are inparticular administered in the form of those pharmaceutical compositionswhich are suitable for topical application. For the production of thepharmaceutical compositions, the compounds of the invention (=activecompounds) are preferably mixed with suitable pharmaceutical auxiliariesand further processed to give suitable pharmaceutical formulations.Suitable pharmaceutical formulations are, for example, powders,emulsions, suspensions, sprays, oils, ointments, fatty ointments,creams, pastes, gels or solutions.

The pharmaceutical compositions according to the invention are preparedby processes known per se. The dosage of the active compounds is carriedout in the order of magnitude customary for inhibitors of cellularproliferation or apoptosis inducers. Topical application forms (such asointments) for the treatment of dermatoses thus contain the activecompounds in a concentration of, for example, 0.1-99%. The customarydose in the case of systemic therapy (p.o.) is between 0.3 and 30 mg/kgper day, (i.v.) is between 0.3 and 30 mg/kg/h.

Biological Investigations

The anti-proliferative/cytotoxic activity of the compounds describedherein, can be tested on NCl-H460 non-small cell lung cancer cells usingthe Alamar Blue cell viability assay (described in O'Brien et al. Eur JBiochem 267, 5421-5426, 2000). The compounds are dissolved as 20 mMsolutions in dimethylsulfoxide (DMSO) and subsequently diluted insemi-logarithmic steps. DMSO dilutions are further diluted 1:100 intoDulbecco's modified Eagle's medium (DMEM) containing 10% fetal calfserum to a final concentration twice as much as the final concentrationin the test. NCl-460 cells are seeded into 96 well flat bottom plates ata density of 4000 cells per well in a volume of 50 μl per well. 24 hoursafter seeding the 50 μl each of the compound dilutions in DMEM mediumare added into each well of the 96 Well plate. Each compound dilution istested as quadruplicates. Wells containing untreated control cells arefilled with 50 μl DMEM medium containing 1% DMSO. The cells are thenincubated with the substances for 72 hours at 37° C. In a humifiedatmosphere containing 5% carbon dioxide. To determine the viability ofthe cells, 10 μl of an Alamar Blue solution (Biosource) are added andthe fluorescence is measured at an extinction of 544 nm and an emissionof 590 nm. For the calculation of cell viability the emission value fromuntreated cells is set to 100% viability and the emission rates oftreated cells are set in relation to the values of untreated cells.Viabilities are expressed as % values.

The corresponding IC₅₀ values of the compounds foranti-proliferative/cytotoxic activity are determined from theconcentration-effect curves.

Representative advantageous IC₅₀ values foranti-proliferation/cytotoxicity determined for the compounds mentionedand numbered as Examples in the examples above follow from the followingtable A, in which the numbers of the compound correspond to the numbersof the examples. TABLE A Anti-proliferative/cytotoxic activity −log IC₅₀NCl- Compounds H460 (mol/l) 1, 2, 4, 5, 9, The inhibitory 10, 16, 18,values of these 20, 21, 22, listed Examples 25, 28, 30, lie in the range34 and 36 from 5.5 to 6.4

The induction of apoptosis can be measured by using a Cell deathdetection ELISA (Roche Biochemicals, Mannheim, Germany). NCl-460 cellsare seeded into 96 well flat bottom plates at a density of 10000 cellsper well in a volume of 50 μl per well. 24 hours after seeding the 50 μleach of the compound dilutions in DMEM medium are added into each wellof the 96 Well plate. Each compound dilution is tested at least astriplicates. Wells containing untreated control cells are filled with 50μl DMEM medium containing 1% DMSO. The cells are then incubated with thesubstances for 24 hours at 37° C. in a humidified athmosphere containing5% carbon dioxide. As a positive control for the induction of apoptosis,cells are treated with 50 μM Cisplatin (Gry Pharmaceuticals,Kirchzarten, Germany). Medium is then removed and the cells are lysed in200 μl lysis buffer. After centrifugation as described by themanufacturer, 10 μl of cell lysate is processed as described in theprotocol. The degree of apoptosis is calculated as follows: Theabsorbance at 405 nm obtained with lysates from cells treated with 50 μMcisplatin is set as 100 cpu (cisplatin units), while an absorbance at405 nm of 0.0 was set as 0.0 cpu. The degree of apoptosis is expressedas cpu in relation to the value of 100 cpu reached with the lysatesobtained from cells treated with 50 μM cisplatin.

1. A compound of formula I

in which R1 is halogen, nitro, amino, mono- or di-1-4C-alkylamino,1-4C-alkyl, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, R2 is hydrogen, halogen or1-4C-alkoxy, and R3 is hydrogen or 1-4C-alkoxy, or R2 and R3 bound tothe benzo ring moiety in ortho-position to each other together form a1-2C-alkylenedioxy bridge, or R2 and R3 bound to the benzo ring moietyin ortho-position to each other together form a completely orpredominantly fluorine-substituted 1-2C-alkylenedioxy bridge, or R1 andR2 bound to the benzo ring moiety in ortho-position to each othertogether form a 1-2C-alkylenedioxy bridge and R3 is hydrogen, or R1 andR2 bound to the benzo ring moiety in ortho-position to each othertogether form a completely or predominantly fluorine-substituted1-2C-alkylenedioxy bridge and R3 is hydrogen, R4 is hydrogen, fluorine,chlorine, 1-4C-alkyl, trifluoromethyl, cyclopropyl, cyano,1-4C-alkoxycarbonyl or —CH₂—O—R411, in which R411 is hydrogen,1-4C-alkyl, 1-4C-alkoxy-2-4-alkyl or 1-4C-alkylcarbonyl, R41 is hydrogenor 1-4C-alkyl, R5 is hydrogen, and R51 is hydrogen, or R4 is hydrogen,fluorine, chlorine or 1-4C-alkyl, R41 is hydrogen or 1-4C-alkyl, R5 ishydrogen, and R51 is hydrogen, R6 is 1-6C-alkyl, amino, formyl, or1-4C-alkyl substituted by R61, in which R61 is 1-4C-alkoxycarbonyl,carboxyl, 1-4C-alkoxy, hydroxyl, halogen or —N(R611)R612, in which R611is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,and R612 is hydrogen or 1-4C-alkyl, or R611 and R612 together and withinclusion of the nitrogen atom to which they are bound form a radicalHet1, in which Het1 is a 5- to 7-membered saturated heterocyclic ringradical comprising one nitrogen atom, to which R611 and R612 are bound,and, optionally, one further heteroatom selected from the groupconsisting of nitrogen, oxygen and sulfur, and optionally substituted byR613 on a ring nitrogen atom, in which R613 is 1-4C-alkyl,3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-2-4C-alkyl,1-4C-alkoxy-2-4C-alkyl, amino-2-4C-alkyl, mono- ordi-1-4C-alkylamino-2-4C-alkyl, formyl, pyridyl or pyrimidinyl, R7 isphenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl, R74-and/or R75-substituted Het2, naphthyl, or R76- and/or R77-substitutednaphthyl, in which Het2 is a monocyclic or fused bicyclic 5 to10-membered heteroaryl radical comprising one to three heteroatoms, eachof which is selected from the group consisting of nitrogen, oxygen andsulfur, R71 is hydroxyl, halogen, nitro, cyano, trifluoromethyl,1-4C-alkyl, 1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino,1-4C-alkylsulphonylamino, arylsulphonylamino, 1-4C-alkoxycarbonyl,carboxyl, 1-4C-alkylthio, aryloxy-2-4C-alkoxy, aryloxy-1-4C-alkyl,aryloxy, aryl-1-4C-alkoxy, aryl, 1-4C-alkoxy-2-4C-alkoxy,1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkoxy, amino-2-4C-alkoxy, mono- ordi-1-4C-alkylamino-2-4C-alkoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, in which aryl is phenyl orR711-substituted phenyl, in which R711 is halogen, 1-4C-alkyl,1-4C-alkoxy, nitro or cyano, R72 is halogen, 1-4C-alkyl, 1-4C-alkoxy or1-4C-alkoxycarbonyl, R73 is 1-4C-alkyl or 1-4C-alkoxy, R74 is halogen,1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, cyano, amino, mono- ordi-1-4C-alkylamino, 1-4C-alkoxycarbonyl, morpholino, carboxyl, nitro,phenyl or phenyloxy, R75 is 1-4C-alkyl or halogen, R76 is halogen,hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, carboxyl or 1-4C-alkoxycarbonyl, R77is 1-4C-alkyl or 1-4C-alkoxy, R8 is phenyl, phenylcarbonyl,—C(O)—N(R82)R83 or —C(O)—OR9, in which R82 is hydrogen, 1-4C-alkyl,3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, phenyl orphenyl-1-4C-alkyl, and R83 is hydrogen or 1-4C-alkyl, or R82 and R83together and with inclusion of the nitrogen atom, to which they arebound, form a heterocyclic ring radical selected from the groupconsisting of pyrrolidinyl, piperidinyl, morpholinyl andN-(1-4C-alkyl)-piperazinyl, R9 is 1-4C-alkyl, or a salt, stereoisomer,hydrate or hydrate of a salt thereof; under the proviso that thissubgroup of compounds of formula I, wherein the combination of all ofthe following restrictions a.) to c.) apply, is thereof disclaimed: a.)the substitution pattern of the left R1- and/or R2- and/orR3-substituted benzo ring of the dihydroisoquinoline moiety of thepyrrolodihydroisoquinoline scaffold shown in formula I is as follows:

in which R′ and R″ can be bonded at any possible position of the benzoring, and R′ is hydroxyl, 1-4C-alkoxy or trifluoromethoxy, R″ ishydrogen or 1-4C-alkoxy, or R′ and R″ bound to the benzo ring moiety inortho-position to each other together form a 1-2C-alkylenedioxy bridge,and b.) R4 is hydrogen, and R41 is hydrogen, and R5 is hydrogen, and R51is hydrogen, and c.) R8 is —C(O)—OR9, in which R9 is 1-4C-alkyl.
 2. Acompound of formula I according to claim 1, in which R1 is halogen,nitro, amino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, orcompletely or predominantly fluorine-substituted 1-4C-alkoxy, R2 is1-4C-alkoxy, R3 is hydrogen, and none of R1, R2 and R3 is bound to the10-position of the pyrrolo[2,1-a]-isoquinoline ring, R4 is hydrogen or1-4C-alkyl, R41 is hydrogen or 1-4C-alkyl, R5 is hydrogen, R51 ishydrogen, R6 is 1-6C-alkyl, formyl, or 1-4C-alkyl substituted by R61, inwhich R61 is 1-4C-alkoxycarbonyl, R7 is phenyl, Het2, R71- and/or R72-and/or R73-substituted phenyl, R74- and/or R75-substituted Het2, ornaphthyl, in which Het2 is a heteroaryl radical selected from the groupconsisting of furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl,indolyl, benzothiophenyl and benzofuranyl, R71 is hydroxyl, 1-4C-alkoxy,amino or mono- or di-1-4C-alkylamino, R72 is 1-4C-alkyl or 1-4C-alkoxy,R73 is 1-4C-alkyl or 1-4C-alkoxy, R74 is 1-4C-alkyl, trifluoromethyl,1-4C-alkoxy, 1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy, R75 is1-4C-alkyl, R8 is phenyl, phenylcarbonyl, or —C(O)—N(R82)R83, in whichR82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl, and R83 ishydrogen or 1-4C-alkyl, or R82 and R83 together and with inclusion ofthe nitrogen atom, to which they are bound, form a heterocyclic ringradical selected from the group consisting of pyrrolidinyl andpiperidinyl, or a salt, stereoisomer, hydrate or hydrate of a saltthereof.
 3. A compound of formula I according to claim 1, in which R1 ishalogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkoxy, orcompletely or predominantly fluorine-substituted 1-4C-alkoxy, with theprovisio that R1 is not trifluoromethoxy, R2 is 1-4C-alkoxy, and R3 ishydrogen, or R1 and R2 bound to the benzo ring moiety in ortho-positionto each other together form a completely or predominantlyfluorine-substituted 1-2C-alkylenedioxy bridge and R3 is hydrogen, andnone of R1, R2 and R3 is bound to the 10-position of thepyrrolo[2,1-a]-isoquinoline ring, R4 is hydrogen or 1-4C-alkyl, R41 ishydrogen or 1-4C-alkyl, R5 is hydrogen, R51 is hydrogen, R6 is1-6C-alkyl, formyl, or 1-4C-alkyl substituted by R61, in which R61 is1-4C-alkoxycarbonyl, R7 is phenyl, Het2, R71- and/or R72- and/orR73-substituted phenyl, R74- and/or R75-substituted Het2, or naphthyl,in which Het2 is a heteroaryl radical selected from the group consistingof furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,benzothiophenyl and benzofuranyl, R71 is hydroxyl, 1-4C-alkoxy, amino ormono- or di-1-4C-alkylamino, R72 is 1-4C-alkyl or 1-4C-alkoxy, R73 is1-4C-alkyl or 1-4C-alkoxy, R74 is 1-4C-alkyl, trifluoromethyl,1-4C-alkoxy, 1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy, R75 is1-4C-alkyl, R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9,in which R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl, and R83is hydrogen or 1-4C-alkyl, or R82 and R83 together and with inclusion ofthe nitrogen atom, to which they are bound, form a heterocyclic ringradical selected from the group consisting of pyrrolidinyl andpiperidinyl, R9 is 1-4C-alkyl, or a salt, stereoisomer, hydrate orhydrate of a salt thereof.
 4. A compound of formula I according to claim1, in which R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,1-4C-alkoxy-2-4C-alkoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, R2 is 1-4C-alkoxy, R3 is 1-4C-alkoxy,and none of R1, R2 and R3 is bound to the 10-position of thepyrrolo[2,1-a]-isoquinoline ring, R4 is hydrogen or 1-4C-alkyl, R41 ishydrogen or 1-4C-alkyl, R5 is hydrogen, R51 is hydrogen, R6 is1-6C-alkyl, formyl, or 1-4C-alkyl substituted by R61, in which R61 is1-4C-alkoxycarbonyl, R7 is phenyl, Het2, R71- and/or R72- and/orR73-substituted phenyl, R74- and/or R75-substituted Het2, or naphthyl,in which Het2 is a heteroaryl radical selected from the group consistingof furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolyl, indolyl,benzothiophenyl and benzofuranyl, R71 is hydroxyl, 1-4C-alkoxy, amino ormono- or di-1-4C-alkylamino, R72 is 1-4C-alkyl or 1-4C-alkoxy, R73 is1-4C-alkyl or 1-4C-alkoxy, R74 is 1-4C-alkyl, trifluoromethyl,1-4C-alkoxy, 1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy, R75 is1-4C-alkyl, R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9,in which R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl, and R83is hydrogen or 1-4C-alkyl, or R82 and R83 together and with inclusion ofthe nitrogen atom, to which they are bound, form a heterocyclic ringradical selected from the group consisting of pyrrolidinyl andpiperidinyl, R9 is 1-4C-alkyl, or a salt, stereoisomer, hydrate orhydrate of a salt thereof.
 5. A compound of formula I according to claim1, in which R1 is halogen, nitro, amino, 1-4C-alkyl, 1-4C-alkoxy,1-4C-alkoxy-2-4C-alkoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, R2 is 1-4C-alkoxy, R3 is hydrogen, andnone of R1, R2 and R3 is bound to the 10-position of thepyrrolo[2,1-a]-isoquinoline ring, R4 is 1-4C-alkyl, R41 is hydrogen or1-4C-alkyl, R5 is hydrogen, R51 is hydrogen, R6 is 1-6C-alkyl, formyl,or 1-4C-alkyl substituted by R61, in which R61 is 1-4C-alkoxycarbonyl,R7 is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl, R74-and/or R75-substituted Het2, or naphthyl, in which Het2 is a heteroarylradical selected from the group consisting of furanyl, thiophenyl,pyrrolyl, pyridinyl, quinolyl, indolyl, benzothiophenyl andbenzofuranyl, R71 is hydroxyl, 1-4C-alkoxy, amino or mono- ordi-1-4C-alkylamino, R72 is 1-4C-alkyl or 1-4C-alkoxy, R73 is 1-4C-alkylor 1-4C-alkoxy, R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy, R75 is 1-4C-alkyl, R8is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9, in which R82 ishydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl, and R83 is hydrogen or1-4C-alkyl, or R82 and R83 together and with inclusion of the nitrogenatom, to which they are bound, form a heterocyclic ring radical selectedfrom the group consisting of pyrrolidinyl and piperidinyl, R9 is1-4C-alkyl, or a salt, stereoisomer, hydrate or hydrate of a saltthereof.
 6. A compound of formula I according to claim 1, in which, in afirst embodiment, R1 is halogen, nitro, amino, mono- ordi-1-4C-alkylamino, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkoxy,3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, R2 is 1-4C-alkoxy, R3 is hydrogen, andnone of R1 and R2 is bound to the 10-position of thepyrrolo[2,1-a]-isoquinoline ring, and R4 is hydrogen, R41 is hydrogen,R5 is hydrogen, and R51 is hydrogen; or in which, in a secondembodiment, R1 is 1-4C-alkoxy, R2 is 1-4C-alkoxy, R3 is hydrogen, andnone of R1 and R2 is bound to the 10-position of thepyrrolo[2,1-a]isoquinoline ring, and R4 is 1-4C-alkyl, R41 is hydrogenor 1-4C-alkyl, R5 is hydrogen, and R51 is hydrogen; R6 is 1-6C-alkyl, or1-4C-alkyl substituted by R61, in which R61 is 1-4C-alkoxycarbonyl; R7is Het2,4-hydroxy-3,5-dimethylphenyl, 3-dimethylamino-phenyl, ornaphthyl, in which Het2 is a monocyclic or fused bicyclic 5- to10-membered heteroaryl radical comprising one to three heteroatoms, eachof which is selected from the group consisting of nitrogen, oxygen andsulfur; R8 is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9, inwhich R82 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl, and R83 ishydrogen or 1-4C-alkyl, or R82 and R83 together and with inclusion ofthe nitrogen atom, to which they are bound, form a heterocyclic ringradical selected from the group consisting of pyrrolidinyl andpiperidinyl, R9 is 1-4C-alkyl; or a salt, stereoisomer, hydrate orhydrate of a salt thereof.
 7. A compound of formula I according to claim1, in which, in a first embodiment, R1 is halogen,1-4C-alkoxy-2-4C-alkoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, R2 is 1-4C-alkoxy, R3 is hydrogen, andnone of R1 and R2 is bound to the 7- or 10-position of thepyrrolo[2,1-a]-isoquinoline ring, and R4 is hydrogen, R41 is hydrogen,R5 is hydrogen, and R51 is hydrogen; or in which, in a secondembodiment, R1 is 1-4C-alkoxy, R2 is 1-4C-alkoxy, R3 is hydrogen, andnone of R1 and R2 is bound to the 7- or 10-position of thepyrrolo[2,1-a]-isoquinoline ring, and R4 is 1-4C-alkyl, R41 is hydrogenor 1-4C-alkyl, R5 is hydrogen, and R51 is hydrogen; R6 is 1-4C-alkyl, or1-4C-alkyl substituted by R61, in which R61 is 1-4C-alkoxycarbonyl; R7is Het2,4-hydroxy-3,5-dimethylphenyl, 3-dimethylamino-phenyl, ornaphthyl, in which Het2 is a monocyclic or fused bicyclic 5- to10-membered heteroaryl radical comprising one to three heteroatoms, eachof which is selected from the group consisting of nitrogen, oxygen andsulfur, R8 is —C(O)—OR9, in which R9 is 1-4C-alkyl; or a salt,stereoisomer, hydrate or hydrate of a salt thereof.
 8. A compound offormula I according to claim 1, in which, in a first embodiment, eitherR1 is halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, orcompletely or predominantly fluorine-substituted 1-4C-alkoxy, R2 is1-4C-alkoxy, and R3 is 1-4C-alkoxy, or R1 is 1-4C-alkoxy,1-4C-alkoxy-2-4C-alkoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, R2 is halogen, and R3 is 1-4C-alkoxy,and none of R1, R2 and R3 is bound to the 10-position of thepyrrolo[2,1-a]-isoquinoline ring; or either R1 is halogen, 1-4C-alkyl,1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, R2 is 1-4C-alkoxy, and R3 is hydrogen,or R1 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, or completely orpredominantly fluorine-substituted 1-4C-alkoxy, R2 is halogen, and R3 ishydrogen, and none of R1 and R2 is bound to the 7- or 10-position of thepyrrolo[2,1-a]-isoquinoline ring; and R4 is 1-4C-alkyl, R41 is hydrogenor 1-4C-alkyl, R5 is hydrogen, and R51 is hydrogen; or in which, in asecond embodiment, R1 is 1-4C-alkoxy, R2 is 1-4C-alkoxy, R3 is hydrogen,and none of R1 and R2 is bound to the 7- or 10-position of thepyrrolo[2,1-a]-isoquinoline ring, and R4 is 1-4C-alkyl, R41 is hydrogenor 1-4C-alkyl, R5 is hydrogen, R51 is hydrogen; R6 is 1-6C-alkyl, or1-4C-alkyl substituted by R61, in which R61 is 1-4C-alkoxycarbonyl, R7is phenyl, Het2, R71- and/or R72- and/or R73-substituted phenyl, R74-and/or R75-substituted Het2, or naphthyl, in which Het2 is a heteroarylradical selected from the group consisting of furanyl, thiophenyl,pyrrolyl, pyridinyl, quinolyl, indolyl, benzothiophenyl andbenzofuranyl, R71 is hydroxyl, 1-4C-alkoxy, amino or mono- ordi-1-4C-alkylamino, R72 is 1-4C-alkyl or 1-4C-alkoxy, R73 is 1-4C-alkylor 1-4C-alkoxy, R74 is 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,1-4C-alkoxycarbonyl, nitro, phenyl or phenyloxy, R75 is 1-4C-alkyl, R8is phenyl, phenylcarbonyl, —C(O)—N(R82)R83 or —C(O)—OR9, in which R82 ishydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or phenyl, and R83 is hydrogen or1-4C-alkyl, or R82 and R83 together and with inclusion of the nitrogenatom, to which they are bound, form a heterocyclic ring radical selectedfrom the group consisting of pyrrolidinyl and piperidinyl, R9 is1-4C-alkyl, or a salt, stereoisomer, hydrate or hydrate of a saltthereof.
 9. A compound of formula I according to claim 1, in which R1 ishalogen, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, or completely orpredominantly fluorine-substituted 1-4C-alkoxy, R2 is 1-4C-alkoxy, R3 is1-4C-alkoxy, and none of R1, R2 and R3 is bound to the 10-position ofthe pyrrolo[2,1-a]-isoquinoline ring, and R4 is hydrogen, or 1-4C-alkylR41 is hydrogen, or 1-4C-alkyl R5 is hydrogen, and R51 is hydrogen; orR1 is halogen, 1-4C-alkoxy-2-4C-alkoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, R2 is 1-4C-alkoxy, R3 is hydrogen, andnone of R1, R2 and R3 is bound to the 10-position of thepyrrolo[2,1-a]-isoquinoline ring, and R4 is hydrogen, or 1-4C-alkyl, R41is hydrogen, or 1-4C-alkyl, R5 is hydrogen, and R51 is hydrogen; or R1is 1-4C-alkoxy, R2 is 1-4C-alkoxy, R3 is hydrogen, and none of R1, R2and R3 is bound to the 10-position of the pyrrolo[2,1-a]-isoquinolinering, and R4 is 1-4C-alkyl, R41 is hydrogen, or 1-4C-alkyl, R5 ishydrogen, and R51 is hydrogen; R6 is 1-4C-alkyl, R7 is4-hydroxy-3,5-dimethylphenyl, 3-dimethylamino-phenyl, or pyridyl,indolyl, thiophenyl, quinolinyl or naphthyl, R8 is —C(O)—OR9, in whichR9 is 1-2C-alkyl, or a salt, stereoisomer, hydrate or hydrate of a saltthereof.
 10. A compound of formula I according to claim 1, in which, ina first embodiment, either R1 is bonded in the 8-position of thepyrrolo[2,1-a]-isoquinoline ring, and is chlorine, 2-methoxy-ethoxy ordifluoromethoxy, and R2 is bonded in the 9-position of thepyrrolo[2,1-a]-isoquinoline ring, and is methoxy, or R1 is bonded in the9-position of the pyrrolo[2,1-a]-isoquinoline ring, and is chlorine,fluorine, methyl, nitro, amino or difluoromethoxy, and R2 is bonded inthe 8-position of the pyrrolo[2,1-a]-isoquinoline ring, and is methoxy,and R3 is hydrogen, and either R4 is hydrogen, R41 is hydrogen, R5 ishydrogen, and R51 is hydrogen, or R4 is methyl, R41 is hydrogen ormethyl, R5 is hydrogen, and R51 is hydrogen; or in which, in a secondembodiment, R1 is bonded in the 8-position of thepyrrolo[2,1-a]-isoquinoline ring, and is methoxy, R2 is bonded in the9-position of the pyrrolo[2,1-a]-isoquinoline ring, and is methoxy, R3is hydrogen, and R4 is methyl, R41 is hydrogen or methyl, R5 ishydrogen, R51 is hydrogen; R6 is methyl or 2-methoxycarbonylethyl, R7 is4-hydroxy-3,5-dimethylphenyl, 3-dimethylamino-phenyl,3,4,5-trimethoxyphenyl, quinolinyl or naphthyl, R8 is phenylcarbonyl,—C(O)—N(R82)R83 or —C(O)—OR9, in which R82 is hydrogen, methyl, ethyl,iso-propyl, iso-butyl, cyclohexyl, cyclopropyl or phenyl, and R83 ishydrogen or methyl, or R82 and R83 together and with inclusion of thenitrogen atom, to which they are bound, form a pyrrolidinyl radical, R9is methyl or ethyl, or a salt, stereoisomer, hydrate or hydrate of asalt thereof.
 11. A compound according to claim 1, wherein saidcompounds have the formula I, in which R1 is 1-4C-alkoxy, R2 is1-4C-alkoxy, R3 is hydrogen, and none of R1 and R2 is bound to the 7- or10-position of the pyrrolo[2,1-a]-isoquinoline ring, and in which R4 is1-4C-alkyl, R41 is hydrogen, or 1-4C-alkyl, R5 is hydrogen, R51 ishydrogen, or a salt, stereoisomer, hydrate or hydrate of a salt thereof.12. A compound according to claim 1, wherein said compounds have theformula I, in which either R1 is halogen, nitro, amino, mono- ordi-1-4C-alkylamino, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkoxy,3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, and R2 is 1-4C-alkoxy, or R1 is1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, 3-7C-cycloalkoxy,3-7C-cycloalkylmethoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, and R2 is halogen, and R3 is hydrogen,and none of R1 and R2 is bound to the 7- or 10-position of thepyrrolo[2,1-a]-isoquinoline ring; and in which either R4 is hydrogen,R41 is hydrogen, R5 is hydrogen, and R51 is hydrogen, or R4 is1-4C-alkyl, R41 is hydrogen or 1-4C-alkyl, R5 is hydrogen, and R51 ishydrogen; or a salt, stereoisomer, hydrate or hydrate of a salt thereof.13. A compound according to claim 1, wherein said compounds have theformula I, in which either R1 is halogen, nitro, amino, mono- ordi-1-4C-alkylamino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, and R2 is 1-4C-alkoxy, or R1 is1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, 3-7C-cycloalkoxy,3-7C-cycloalkylmethoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, and R2 is halogen, and R3 is1-4C-alkoxy, and none of R1, R2 and R3 is bound to the 10-position ofthe pyrrolo[2,1-a]-isoquinoline ring; and in which either R4 ishydrogen, R41 is hydrogen, R5 is hydrogen, and R51 is hydrogen, or R4 is1-4C-alkyl, R41 is hydrogen or 1-4C-alkyl, R5 is hydrogen, and R51 ishydrogen; or a salt, stereoisomer, hydrate or hydrate of a salt thereof.14. A compound according to claim 1, wherein said compounds have theformula I, in which R1 is halogen, 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,or completely or predominantly fluorine-substituted 1-4C-alkoxy, R2 is1-4C-alkoxy, R3 is 1-4C-alkoxy, and none of R1, R2 and R3 is bound tothe 10-position of the pyrrolo[2,1-a]-isoquinoline ring, and R4 ishydrogen, or 1-4C-alkyl, R41 is hydrogen, or 1-4C-alkyl, R5 is hydrogen,and R51 is hydrogen; or R1 is halogen, 1-4C-alkoxy-2-4C-alkoxy, orcompletely or predominantly fluorine-substituted 1-4C-alkoxy, R2 is1-4C-alkoxy, R3 is hydrogen, and none of R1, R2 and R3 is bound to the10-position of the pyrrolo[2,1-a]-isoquinoline ring, and R4 is hydrogen,or 1-4C-alkyl, R41 is hydrogen, or 1-4C-alkyl, R5 is hydrogen, and R51is hydrogen; or R1 is 1-4C-alkoxy, R2 is 1-4C-alkoxy, R3 is hydrogen,and none of R1, R2 and R3 is bound to the 10-position of thepyrrolo[2,1-a]-isoquinoline ring, and R4 is 1-4C-alkyl, R41 is hydrogen,or 1-4C-alkyl, R5 is hydrogen, and R51 is hydrogen; and R6 is1-4C-alkyl; or a salt, stereoisomer, hydrate or hydrate of a saltthereof.
 15. A compound according to claim 1, wherein said compoundshave the formula I, in which R1 is fluorine, chlorine,1-2C-alkoxy-2-3C-alkoxy, or completely or predominantlyfluorine-substituted 1-2C-alkoxy, R2 is 1-2C-alkoxy, R3 is hydrogen, andnone of R1 and R2 is bound to the 7- or 10-position of thepyrrolo[2,1-a]-isoquinoline ring, and R4 is hydrogen, R41 is hydrogen,R5 is hydrogen, and R51 is hydrogen; or R1 is 1-2C-alkoxy, R2 is1-2C-alkoxy, R3 is hydrogen, and none of R1 and R2 is bound to the 7- or10-position of the pyrrolo[2,1-a]-isoquinoline ring, and R4 is1-2C-alkyl, R41 is hydrogen, or 1-2C-alkyl, R5 is hydrogen, and R51 ishydrogen; or R1 is fluorine, chlorine, 1-2C-alkoxy-2-3C-alkoxy, orcompletely or predominantly fluorine-substituted 1-2C-alkoxy, R2 is1-2C-alkoxy, R3 is hydrogen, and none of R1 and R2 is bound to the 7- or10-position of the pyrrolo[2,1-a]-isoquinoline ring, and R4 is1-2C-alkyl, R41 is hydrogen, or 1-2C-alkyl, R5 is hydrogen, and R51 ishydrogen; and R6 is 1-2C-alkyl; or a salt, stereoisomer, hydrate orhydrate of a salt thereof.
 16. A compound according to claim 1, whereinsaid compounds have the formula I, in which R1 is fluorine, chlorine,1-2C-alkoxy-2-3C-alkoxy, or completely or predominantlyfluorine-substituted 1-2C-alkoxy, R2 is 1-2C-alkoxy, R3 is hydrogen, andnone of R1 and R2 is bound to the 7- or 10-position of thepyrrolo[2,1-a]-isoquinoline ring, and R4 is 1-2C-alkyl, R41 is hydrogen,or 1-2C-alkyl, R5 is hydrogen, and R51 is hydrogen; or a salt,stereoisomer, hydrate or hydrate of a salt thereof.
 17. A compoundaccording to claim 1, wherein said compounds have the formula I, inwhich R6 is 1-4C-alkyl, R7 is Het2,4-hydroxy-3,5-dimethylphenyl,3-dimethylamino-phenyl, or naphthyl, in which Het2 is a monocyclic orfused bicyclic 5- to 10-membered heteroaryl radical comprising one tothree heteroatoms, each of which is selected from the group consistingof nitrogen, oxygen and sulfur, R8 is —C(O)—OR9, in which R9 is1-4C-alkyl, or a salt, stereoisomer, hydrate or hydrate of a saltthereof.
 18. A compound according to claim 1, wherein said compound isselected from the group consisting of: 1.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3,5,6-trimethyl-5,6-dihydro-pyrrolo[2,1-α]isoquinoline-1-carboxylicacid ethyl ester, 2.(6RS)-2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3,6-dimethyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 3.(6RS)-8,9-Dimethoxy-3,6-dimethyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 4.9-(1,1-Difluoro-methoxy)-2-(3-dimethylamino-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylicacid ethyl ester, 5.9-(1,1-Difluoro-methoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylicacid ethyl ester, 6.9-(1,1-Difluoro-methoxy)-8-methoxy-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylicacid ethyl ester, 7.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9,10-trimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 8.8-(1,1-Difluoro-methoxy)-9-methoxy-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylicacid ethyl ester, 9.8-(1,1-Difluoro-methoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-9-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylicacid ethyl ester, 10.8-(1,1-Difluoro-methoxy)-2-(3-dimethylamino-phenyl)-9-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylicacid ethyl ester, 11.8,9-(1,1-Difluoro-methylenedioxy)-2-(3-dimethylamino-phenyl)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylicacid ethyl ester, 12.8,9-(1,1-Difluoro-methylenedioxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylicacid ethyl ester, 13.8,9-(1,1-Difluoro-methylenedioxy)-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylicacid ethyl ester, 14.9-Chloro-2-(4-hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 15.9-Chloro-8-methoxy-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 16.9-Chloro-2-(3-dimethylamino-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 17.8-Chloro-2-(4-hydroxy-3,5-dimethyl-phenyl)-9-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 18.2-(4-Hydroxy-3,5-dimethyl-phenyl)-9-methoxy-8-(2-methoxy-ethoxy)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 19.9-Methoxy-8-(2-methoxy-ethoxy)-3-methyl-2-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 20.9-Methoxy-8-(2-methoxy-ethoxy)-3-methyl-2-naphthalen-1-yl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 21.9-Fluoro-2-(4-hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 22.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-9-nitro-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 23.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3,9-dimethyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 24.8,9-Dimethoxy-3-(2-methoxycarbonyl-ethyl)-6,6-dimethyl-2-quinolin-4-yl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 25.9-Amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-8-methoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethyl ester, 26.1-[2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinolin-1-yl]-1-phenyl-methanone,27.4-(8,9-Dimethoxy-3-methyl-1-phenyl-5,6-dihydro-pyrrolo[2,1-a]isoquinolin-2-yl)-2,6-dimethyl-phenol,28.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid cyclohexyl amide, 29.1-[2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinolin-1-yl]-1-pyrrollidin-1-yl-methanone,30.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid isopropylamide, 31.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid dimethylamide, 32.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid methylamide, 33.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid amide, 34.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid phenylamide, 35.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid ethylamide, 36.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid sec-butylamide, and 37.2-(4-Hydroxy-3,5-dimethyl-phenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylicacid cyclopropylamide; and the salts, stereoisomers, hydrates, andhydrates of the salts thereof. 19-20. (canceled)
 21. A pharmaceuticalcomposition comprising one or more compounds according to claim 1, or apharmaceutically acceptable salt, stereoisomer, hydrate or hydrate of asalt thereof, together with a customary pharmaceutical excipient and/orvehicle.
 22. A method for treating hyperproliferative diseases of benignor malignant behaviour and/or disorders responsive to the induction ofapoptosis, in a patient comprising administering to said patient atherapeutically effective amount of a compound according to claim 1, ora pharmaceutically acceptable salt, stereoisomer, hydrate or hydrate ofa salt thereof.
 23. The method according to claim 22, wherein saidhyperproliferative disease of benign or malignant behavior and/ordisorder responsive to the induction of apoptosis is cancer.